TW201031663A

TW201031663A - New tetrahydropyrazolo[3,4-c]isoquinolin-5-amine derivatives

Info

Publication number: TW201031663A
Application number: TW099104180A
Authority: TW
Inventors: Moll Joan Taltavull; Ferrer Jordi Gracia; Santacana Lluis Miquel Pages
Original assignee: Almirall Sa
Priority date: 2009-02-27
Filing date: 2010-02-10
Publication date: 2010-09-01
Also published as: EP2226323A1; WO2010097172A1; UY32415A; AR075603A1

Abstract

New tetrahydropyrazolo [3, 4-c] isoquinolin-5- amine derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of the phosphodiesterase IV (PDE4).

Description

201031663 六、發明說明：【發明所屬之技術領域】本發明是關於新穎治療上有效之四氫吡唑並[3,“]異喹啉-5-胺衍生物，其製備方法以及包括其之醫藥組合物。此等化合物是構酸二酯酶4 (phosphodiesterase 4 ; PDE4) 之有效以及選擇性抑制劑且因此適用於治療、預防或抑制已知易藉由抑制PDE4來改善之病理學病狀、疾病及病症。【先前技術】填酸二酯酶（phosphodiesterase ; PDE)包括負責使第一4口使環狀單填酸腺皆（cyclic adenosine monophosphate ; cAMP )以及環狀單磷酸鳥苷（cydic guan〇sine monophosphate ; cGMP)水解以及去活化之酶的超家族。迄今為止已鑑別出11種不同pDE家族（PDEi至PDEU)，其不同之處在於受質偏好、催化活性、對内源性活化劑以及抑制劑之敏感性以及編碼基因。 PDE4同功酶（isoenzyme)家族對環狀AMP展現高親和力，但對環狀GMP具有弱親和力。由PDE4抑制引起之環狀AMP含量增加與各種發炎性以及免疫細胞中之細胞活化的抑制相關’所述細胞包含淋巴細胞 (lymphocyte )、巨噬細胞（macr〇phage )、嗜鹼性球 (basophil )、嗜中性白血球（neutrophil)以及嗜伊紅血球 (eosinophil)。此外，PDE4抑制可減少細胞激素腫瘤壞死因子 a (Tumor Necrosis Factor a ; TNFa)之釋放。：PDE4 201031663 之生物學描述於若干個最新評述中，例如M. D. Houslay，P. * Schafer, K. Y. Zhang, Drug Discov Today 2005, 10, 1503-19° 鑒於此等生理作用，近年來已揭露具有不同化學結構之PDE4抑制劑，其用於治療或預防慢性以及急性發炎性疾病以及其他已知易藉由抑制PDE4來改善之病理學病狀、疾病以及病症。例如參見US 5449686、US 5710170、 WO 98/45268、WO 99/06404、WO 01/57025、WO 〇 01/57036 > WO 01/46184 ' WO 97/05105 ' WO 96/40636 ' W003/097613、US 5786354、US 5773467、US 5753666、 US 5728712、US 5693659、US 5679696、US 5596013、US 5541219、US 5508300、US 5502072 或 H. J. Dyke 以及 J. G.201031663 6. Technical Field of the Invention: The present invention relates to a novel therapeutically effective tetrahydropyrazolo[3,"]isoquinolin-5-amine derivative, a preparation method thereof and a medicine therewith Compositions. These compounds are potent and selective inhibitors of phosphodiesterase 4 (PDE4) and are therefore useful for treating, preventing or inhibiting pathological conditions known to be ameliorated by inhibition of PDE4, Diseases and Conditions. [Prior Art] Phosphodiesterase (PDE) is responsible for making the first 4 ports of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cydic guan). 〇sine monophosphate; cGMP) superfamily of enzymes for hydrolysis and deactivation. Eleven different pDE families (PDEi to PDEU) have been identified to date, differing in substrate preference, catalytic activity, endogenous activator And the sensitivity of the inhibitor as well as the coding gene. The PDE4 isoenzyme family exhibits high affinity for cyclic AMP but has weak affinity for cyclic GMP. Increased AMP content is associated with various inflammatory and inhibition of cellular activation in immune cells. 'The cells include lymphocytes, macrophages, basophils, neutrophils. (neutrophil) and eosinophil. In addition, PDE4 inhibition reduces the release of the cytokine Tumor Necrosis Factor a (TNFa). The biology of PDE4 201031663 is described in several recent reviews, such as MD. Houslay, P. * Schafer, KY Zhang, Drug Discov Today 2005, 10, 1503-19° In view of these physiological effects, PDE4 inhibitors having different chemical structures have been disclosed in recent years for the treatment or prevention of chronic and acute inflammation. Sexually transmitted diseases, as well as other pathological conditions, diseases, and conditions known to be ameliorated by inhibition of PDE 4. See, for example, US 5,449, 686, US Pat. No. 5,710,170, WO 98/45268, WO 99/06404, WO 01/57025, WO 〇01/ 57036 > WO 01/46184 'WO 97/05105 'WO 96/40636 'W003/097613, US 5786354, US 5773467, US 5753666, US 5728712, US 5693659, US 5679696, US 5596013, US 5541219, US 5508300, US 5502072 or H. J. Dyke and J. G.

Montana, Exp. Opin. Invest. Drugs 1999, 8, 1301-1325 ° 少數具有選擇性抑制磷酸二酯酶4之能力的化合物正在積極開發中。此等化合物之實例是羅氟司特 (roflumilast)、GSK-256066、阿普司特（apremilast)、替托 ❹ 司特（tetomilast)、咯利普蘭（rolipram)、MK-0873 以及奥格司特（〇glemilast)。已知早期PDE4抑制劑（諸如咯利普蘭）之人類臨床開發已因在治療性血漿含量下出現諸如噁心以及喂吐的副作用而受阻（Curr. Pharm. Des. 2002, 8, 1255-96)。本發明中所述之化合物是降低π區吐可能性之有效以及選擇性 PDE4抑制劑。此性質使其適用於治療或預防病理學病狀 5疾病諸如呼吸道疾病、皮膚病、發炎性疾病、中樞或周邊神經系統疾病以及癌症。此等疾病包含（但不限於） 5 201031663 哮喘、慢性阻塞性肺病（chronic obstructive pulmonary disease)、過敏性鼻炎（allergic也以也）、類風濕性關節炎 (rheumatoid arthritis )、多發性硬化症（multiple sclerosis )、異位性皮膚炎（at〇pic dermatitis)、牛皮癬以及發炎性腸病 (inflammatory bowel disease ) 〇諸如以下稱為本發明之化合物的PDE4抑制劑亦可與其他已知可有效治療此等疾病之藥物組合使用。舉例而言’其可與以下藥物組合使用：支氣管擴張劑 (bronchodilator )，諸如β2·腎上腺素激導性促效劑 (02-adrenergic agonist )、M3蕈毒鹼受體之拮抗劑或結合β2 促效作用與M3拮抗作用之雙重作用分子（dual acting molecule );抗過敏劑（anti-allergic )，諸如抗組織胺劑 (anti-histamine )、肥大細胞穩定劑（mast cell stabilizer )、 CRTH 拮抗劑；消炎劑（anti-inflammatory agent)，諸如皮質類固醇（corticosteroid)、LTD4受體拮抗劑、白三烯合成抑制劑（leukotriene synthesis inhibitor)、COX 抑制劑以及 PDE 抑制劑；免疫抑制劑（immunosuppressive agent)，諸如i弓調神經麟酸酶抑制劑（calcineurin inhibitor )、環孢素 A (cyclosporin A)、雷帕黴素（rapamycin)、T 細胞受體阻斷劑、B細胞受體阻斷劑；以及/或抗感染劑 (antiinfective )，諸如抗生素（antibiotic )、抗黴劑 (antimycotic)、抗病毒劑（antiviral agent)。【發明内容】 201031663 因此 ’本發明提供式、1,化合物或其互變異構體Montana, Exp. Opin. Invest. Drugs 1999, 8, 1301-1325 ° A small number of compounds with the ability to selectively inhibit phosphodiesterase 4 are under active development. Examples of such compounds are roflumilast, GSK-256066, apremilast, tetomilast, rolipram, MK-0873, and augt. (〇glemilast). Human clinical development of early PDE4 inhibitors such as rolipram has been known to be hampered by side effects such as nausea and vomiting at therapeutic plasma levels (Curr. Pharm. Des. 2002, 8, 1255-96). The compounds described in the present invention are effective and selective PDE4 inhibitors for reducing the likelihood of spitting in the π region. This property makes it suitable for the treatment or prevention of pathological conditions such as respiratory diseases, skin diseases, inflammatory diseases, central or peripheral nervous system diseases, and cancer. These diseases include (but are not limited to) 5 201031663 Asthma, chronic obstructive pulmonary disease, allergic rhinitis (allergic also), rheumatoid arthritis (rheumatoid arthritis), multiple sclerosis (multiple) Sclerosis), atopic dermatitis, psoriasis, and inflammatory bowel disease, such as PDE4 inhibitors, hereinafter referred to as compounds of the present invention, may also be effective in treating such The combination of drugs for disease. For example, it can be used in combination with a bronchodilator such as a β2-adrenergic agonist, an antagonist of the M3 muscarinic receptor, or a combination of β2. Dual acting molecule; anti-allergic, such as anti-histamine, mast cell stabilizer, CRTH antagonist; Anti-inflammatory agents, such as corticosteroids, LTD4 receptor antagonists, leukotriene synthesis inhibitors, COX inhibitors and PDE inhibitors; immunosuppressive agents, Such as calcineurin inhibitor, cyclosporin A, rapamycin, T cell receptor blocker, B cell receptor blocker; and / Or antiinfective, such as antibiotics, antimycotic, antiviral agents. SUMMARY OF THE INVENTION 201031663 Accordingly, the present invention provides a compound, a compound, or a tautomer thereof.

❿ φ 其中·· 式⑴ ==縣以及胺基所構成的族群中選出，分支鍵構絲鱗中㈣：氫原子、直鏈或芳基c 、，4rC(〇)崎基團、c“炫基-c5 ,。員含N雜環基、俩基^。芳基Ί之，-二錢㈣芳基、雜芳基以及雜環多個由乂下所構成的族群選出之取代基次夕個炫氧基、經基、較原子、三氟甲基齡基、=基-CM烧基、續醯基_Ci4貌基、“、脸ς燒氧幾观R基團以A_c(〇)NRaRb基團；且 &甲酿基、 •其立地表示氫原子或Ci禮基汉疋由Gw芳基以及含有至少一且 =雜，其子的…。員雜芳基所構成的族群自中所述方基以及所述雜芳基視情況經一 /、中子、h絲以及C1_4純基之取代基取代 < 自幽素原或其醫藥學上可接受之鹽或N氧化物。本發明之其他目的在於提供用於治酸二黯酶IV來改善之病理學病m細鱗 7 201031663 牛皮癬舊本發明亦針對：種醫藥組合物，及醫藥學上可接受之稀釋其包括如上文所定義之化合物以劑或載劑；如上文:===藥r製造供治療 ⑽二ΐ治絲患如上文所定狀病理學病狀或疾病之體的方法’其包括向所述鋪投與有效量之如上文所定義之化合物；以及❿ φ where ·· (1) == selected from the group consisting of the county and the amine group, in the branching skein (4): hydrogen atom, linear or aryl c, 4rC (〇) group, c “Hyun The group -C5, which contains an N-heterocyclic group, a aryl group, an aryl group, a diphthyl (tetra)aryl group, a heteroaryl group, and a heterocyclic ring, and a plurality of substituents selected from the group consisting of the underarms Ethyloxy, thiol, alkaloid, trifluoromethyl-group, thiol-CM alkyl, hydrazine-Ci4, ", ς ς 氧几几 R R R 以以 NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR And & A-branched, • its standing means hydrogen atom or Ci ritual 疋 by Gw aryl and containing at least one and = hetero, its .... The group consisting of a heteroaryl group is substituted from the above-mentioned square group and the heteroaryl group by a substituent of a /, neutron, h-filament and C1_4 pure base < self-pyrolysin or its medicinal Acceptable salts or N oxides. Another object of the present invention is to provide a pathological disease for the treatment of acid diterpene enzyme IV. Fine scales 7 201031663 Psoriasis The present invention also relates to: a pharmaceutical composition, and a pharmaceutically acceptable dilution comprising the above A compound or carrier as defined above; as described above: ===drug r for the treatment of (10) a method for the treatment of a pathological condition or disease as defined above, which includes An effective amount of a compound as defined above;

-、一種組合產物，其包括同時、分別或依序用於治療人體或動物體之（i)如技術方案丨至10中任一項所述之化合物，以及（ii) 一或多種由p2_腎上腺素激導性促效劑、抗膽鹼劑（anti-cholinergic)、抗過敏劑、消炎劑、免疫抑制劑以及抗感染劑所構成的族群選出之活性成份。如本文中所使用，術語Cl_4烷基包含具有1至4個碳原子之直鏈或分支鏈烴基。實例包含甲基、乙基、正丙基、異丙基、正丁基、第二丁基以及第三丁基。如本文中所使用’術語Cm烷氧基包含各具有1至4 個碳原子之直鏈或分支鏈含氡基團。實例包含曱氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、第二丁氧基以及第三丁氧基。如本文中所使用’術語Cm烷氧羰基包含式 ❹ 8 201031663 _C(0)0(C,4烧基)之基團，其中所述Ci 4 個複原子之直賊分支_基。抑包含f輪1 羰基、正丙氧羰基、異丙氧羰基、正丁氧鲈美、=_ 羰基以及第三丁氧羰基。犬土一如本文中所使用，術語C5^ 佳c6_c10單環或多環芳基，諸如較 Ο 基。苯基為較佳。當所述c5 i。‘t j '恩基以及菲卜2或3個可相同或不峰代時’其通常帶有如^文中所使用’術語5至1Q㈣芳基通常包含5 〇貝％系’其包括至少-個雜芳環且含有至少一個選自 u ^以-及N之雜原子。所述雜芳基為單環或兩個或兩個 ^上她，其中至少一個環含有雜原子。當所述5至10 貝雜芳基經取代時，其通常帶有丨、2或3個可相同或不同之取代基。較佳5至10員雜芳基為5至6員雜芳基。5至1〇員雜芳基，實例包含⑽基、鱗基、錢基、令秦基、咬喃基、苯並料基、4二錢、·坐基、、絲、苯並噪唾基、料基、苯㈣錄、料基、嗟二♦基、嗟吩基比洛基、π比咬基、本並嗟唾基、吲哚基、吲唾基、嘌 =基、輕基、異料基、三錢以及& 。為較佳。如本文中所使用，術語5至1〇員含N雜芳基通常包 3 5至1〇員環系，其包括至少一個雜芳環且含有至一個 N原子。所述5至10員含N雜芳基為單環（singie 9 201031663 ring/monocyclic)或兩個或兩個以上稠環（多環），i 少一個環含有N原子。衣’，、中至較佳5至10員含N雜芳基為5至6員含议雜芳基。 5至10員含N雜芳基之實例包含喊基”比嗪基、喷^灵以及噠嗪基。吡啶基為較佳。土a combination product comprising, simultaneously, separately or sequentially for the treatment of a human or animal body (i) a compound according to any one of claims 10 to 10, and (ii) one or more of p2_ An active ingredient selected from the group consisting of an adrenergic agonist, an anti-cholinergic, an anti-allergic agent, an anti-inflammatory agent, an immunosuppressant, and an anti-infective agent. As used herein, the term C1-4 alkyl includes a straight or branched chain hydrocarbon group having from 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and tert-butyl. The term Cm alkoxy as used herein includes a straight or branched chain fluorene containing group each having 1 to 4 carbon atoms. Examples include a decyloxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, a second butoxy group, and a third butoxy group. The term Cm alkoxycarbonyl as used herein, includes a group of the formula 2010 8 201031663 _C(0) 0 (C, 4 alkyl), wherein the Ci 4 complex atoms are cleavage-based. Including f-wheel 1 carbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxyxime, =_carbonyl and tert-butoxycarbonyl. Canine soil As used herein, the term C5^ is preferably a c6_c10 monocyclic or polycyclic aryl group, such as a fluorenyl group. Phenyl is preferred. When the c5 i. 'tj 'Enn and Fib 2 or 3 may or may not be peaked 'which is usually used as used in the text 'The term 5 to 1Q (tetra) aryl usually contains 5 mussels % of the system 'which includes at least one hetero The ring also contains at least one hetero atom selected from the group consisting of u^ and - and N. The heteroaryl group is a single ring or two or two of them, at least one of which contains a hetero atom. When the 5 to 10 shell heteroaryl group is substituted, it usually has an anthracene, 2 or 3 substituents which may be the same or different. Preferably, the 5 to 10 membered heteroaryl group is a 5 to 6 membered heteroaryl group. 5 to 1 member heteroaryl, examples include (10), scaly, ketone, dimethyl, cumyl, benzo, bis, s, s, s, Feeding base, benzene (four) recording, material base, fluorenyl, fluorenylpyryl, π than biting, Benzoindolyl, sulfhydryl, hydrazine, hydrazine, hydrazine, light base, heterogeneous Base, three money and & It is better. As used herein, the term 5 to 1 member containing an N heteroaryl group typically comprises a 35 to 1 member ring system comprising at least one heteroaryl ring and containing to one N atom. The 5 to 10 membered N heteroaryl group is a single ring (singie 9 201031663 ring/monocyclic) or two or more fused rings (polycyclic), and one less ring contains an N atom. Preferably, the 5 to 10 member-containing N heteroaryl group is a 5- to 6-membered heteroaryl group. Examples of the 5- to 10-membered N-containing heteroaryl group include a pyridyl group, a pyridyl group, a pyridazine group, and a pyridazinyl group. Pyridyl groups are preferred.

如本文中所使用，術語5至10員含Ν雜環基含非芳族、飽和或不飽和C5_C1G碳環系，諸如5、6 員基團，其中-個碳原子經N置換且視情況—或多個^ 如1、2、3或4個’較佳為1或2個）其他碳原子經多個選自N以及Ο (較佳0)之其他雜原子置換。因此，較佳地，所述5至10員含N雜環基通常含有丨'個氮原子以及0或1個氧原子。飽和雜環為較佳。、較佳5至1G員含N雜環基為5至6 M含N雜環基。實例包含氮雜環丁烧基（azetidyl)、哌啶基、n比洛咬基、吡咯啉基、哌嗪基、嗎啉基、硫代嗎啉基以及吡唑^基 (pirazolidinyl)。嗎琳基為較佳實例。As used herein, the term 5 to 10 member-containing heterocyclic group contains a non-aromatic, saturated or unsaturated C5_C1G carbocyclic ring system, such as a 5, 6 member group, wherein - one carbon atom is replaced by N and optionally - Or a plurality of ^, such as 1, 2, 3 or 4 'preferably 1 or 2) other carbon atoms are replaced by a plurality of other heteroatoms selected from N and oxime (preferably 0). Accordingly, preferably, the 5 to 10 membered N-containing heterocyclic group usually contains 丨' nitrogen atoms and 0 or 1 oxygen atoms. Saturated heterocycles are preferred. Preferably, the 5 to 1 G member-containing N heterocyclic group is a 5 to 6 M N-containing heterocyclic group. Examples include azetidyl, piperidinyl, npirinyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, and pirazolidinyl.琳琳基 is a preferred example.

如本文中所使用，術語齒素原子包含氣、敦、演或職原子’通常為氟、氯賴原子。術語s基在用作字首時具有相同含義。 ~ 當R2表示綠‘。料、Ci禮基·5至丨〇員含 N雜芳基或烧基·5至1M含N雜環基時，應瞭解所述（^4烧，較佳與如式⑴中所示之分子的氣原子鍵結。當R表不石黃醯基，C5_10芳基或石黃酿基a燒基時，應瞭解S原子較佳與如式⑴切私分子的㈣子鍵結。 10 201031663 、雜絲麵物Lc"院基杨醯基α烧基取代時，麟解s原子較佳美芳基或雜環基鍵結。當r2表示^^ r 表丁之方基、雜芳基或雜環基經 C"基取代k ’應瞭解所魏氧縣之麟碳與芳基、雜芳基或雜環基鍵結。As used herein, the term dentate atom contains a gas, a dioxin, or an atom. The term s base has the same meaning when used as a prefix. ~ When R2 means green ‘. When the compound, Ci et al. 5 to an employee containing an N heteroaryl group or a pyridyl group, 5 to 1 M, an N-containing heterocyclic group, it is understood that the compound is as shown in the formula (1). When the R table is not scutane, C5_10 aryl or stellite a, it should be understood that the S atom is preferably bonded to the (four) sub-bond of the molecule (1). 10 201031663 When the noodle Lc" is substituted by the aryl group, the s atom is preferably a aryl or heterocyclic bond. When r2 represents a square, a heteroaryl or a heterocyclic group of the ^^r, the C" The base substitution k ' should be understood to be bonded to the aryl, heteroaryl or heterocyclic group.

“如本文中所使用，術語醫藥學上可接受之鹽包含與醫樂學上可淑之酸紐形成的鹽。w藥學上可接受之酸包含無機酸’例如舰、硫酸、磷酸、二鱗酸、氮演酸、氫埃酸以及雜；以及有触，例如檸魏、反丁稀二酸、順丁烯二酸、蘋果酸、杏仁酸、抗壞血酸、草酸、丁二酸、酒1酸、苯甲酸、乙酸、曱橫酸、乙績酸、苯石黃酸、環己胺磺酸（cyclohexylsulfamic/cyclamic)或對甲苯磺酸。醫藥學上可接文之驗包含鹼金屬（例如納或鉀）以及驗土金屬（例如#5或鎮）氫氧化物；以及有機驗，例如烧基胺、芳基烷基胺以及雜環胺。本發明之其他較佳鹽為四級銨化合物，其中陰離子 (X )之當量與N原子之正電荷相關。χ-可為各種無機酸之陰離子，例如氯離子、溴離子、碘離子、硫酸根、硝酸根、磷酸根；或有機酸之陰離子，例如乙酸根、順丁烯二酸根、反丁烯二酸根、檸檬酸根、草酸根、丁二酸根、酒石酸根、蘋果酸根、杏仁酸根、三氟乙酸根、甲磺酸根以及對甲苯續酸根。χ-較佳為選自以下之陰離子：氯離子、溴離子、碘離子、硫酸根、硝酸根、乙酸根、順丁烯二酸根、草酸根、丁二酸根或三氟乙酸根。更佳χ-為氯離子、 11 201031663 漠離:發，酸根或甲續酸根。等互變異化合物之互變異構體。通常，此 R3 R2"As used herein, the term pharmaceutically acceptable salt comprises a salt formed with a medically acceptable acid. w A pharmaceutically acceptable acid comprises a mineral acid such as a ship, sulfuric acid, phosphoric acid, or a scale. Acid, nitrogen acid, hydrogen acid and impurities; and touch, such as citrus, antibutanic acid, maleic acid, malic acid, mandelic acid, ascorbic acid, oxalic acid, succinic acid, alcoholic acid, Benzoic acid, acetic acid, hydrazine acid, acetylic acid, benzoic acid, cyclohexylsulfamic/cyclamic or p-toluenesulfonic acid. Pharmaceutically acceptable tests include alkali metals (such as sodium or potassium) And a soil-checking metal (eg #5 or town) hydroxide; and an organic test, such as a sulfhydrylamine, an arylalkylamine, and a heterocyclic amine. Other preferred salts of the invention are quaternary ammonium compounds, of which anions The equivalent of (X) is related to the positive charge of N atom. χ- can be an anion of various inorganic acids, such as chloride, bromide, iodide, sulfate, nitrate, phosphate; or an anion of an organic acid, such as acetic acid Root, maleate, fumaric acid , citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, mesylate and p-toluene sulphate. χ - preferably an anion selected from the group consisting of chloride, bromide , iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably χ - is chloride, 11 201031663 Desert: hair, acid or continuation Acid. A tautomer of a tautomeric compound. Usually, this R3 R2

其中X為〇或ΝΗ〇χ較佳為〇。。為0Wherein X is 〇 or ΝΗ〇χ is preferably 〇. . Is 0

至10員含原子、Cl-4烧基_C5-H)芳基、Cm絲4 中所述芳其私土、Cl·4烷基_5至10員含N雜環基，其燒氧基?基収轉基視情驗—或兩個由LUp to 10 members containing an atom, Cl-4 alkyl group _C5-H) aryl group, Cm wire 4 described in the aryl group, Cl.4 alkyl group 5 to 10 member containing N heterocyclic group, its alkoxy group ?Based on the basis of the test - or two by L

c”醯基所構成:=取ί= 二兀基-本基’其中所述苯基經由羧基、？氧幾基、氰基胺3甲醯基所構成職群選出之取代基單取代。 R通吊表示視情況經一或兩個選自氟原子、氣原子以及甲基之取代基取代的5至1〇員雜芳基。R3較佳表示視 If况經一或兩個選自氯原子以及甲基之取代基取代的吡啶基。R3更佳表示經兩個氣原子取代之吼啶基。在本發明之一較佳實施例中，R1表示羥基；R2表示 ci·4烷基-苯基，其中所述苯基經由羧基、甲氧羰基、氰基 12 以及胺甲酿基所構咸的族群選出之取代基單取代；且尺表不經兩個氯原子取代之吡啶。The structure of c" thiol: = ί = dimercapto-benyl' wherein the phenyl group is monosubstituted by a substituent selected from the group consisting of a carboxyl group, an oxo group and a cyanoamine 3 mercapto group. Hanging means a 5- to 1-membered heteroaryl group optionally substituted with one or two substituents selected from the group consisting of a fluorine atom, a gas atom and a methyl group. R3 preferably represents one or two selected from a chlorine atom. And a pyridyl group substituted with a substituent of a methyl group. R3 more preferably represents an acridinyl group substituted with two gas atoms. In a preferred embodiment of the invention, R1 represents a hydroxyl group; and R2 represents a ci.4 alkyl-benzene group. a group wherein the phenyl group is monosubstituted by a substituent selected from the group consisting of a carboxyl group, a methoxycarbonyl group, a cyano group 12, and an amine-branched group; and a pyridine having no chlorine atom substituted by two chlorine atoms.

201031663 在，發明之另—較佳實補巾，r1表稍基或胺基； R表不氫原子’甲基，-CH2CONH2基團，吼淀-3-基呷基，，情況經-個由甲氧基、縣、甲氧幾基、胺甲醯基以及亂基所f朗鱗㈣之取代絲代的苯T基，視情況經個$氰基以及胺甲醯基所構成的族群選出之取代基取代的3_苯丙基’3供嗎琳基)丙基或3仁甲基胺甲贐基) 酿基；且R3表示3,5_二氣α比咬_4_基。本發明之特定個別化合物包含： 5_(3,5-二氯吡啶斗基胺基)-Μ·二曱基_6,7,8,9,氫 -3Η·-比哇並[3,4-c]異喹啉小醇； N -(3,5-二氯吡啶_4_基)_8,8_二曱基_6,7,8,9_四氣_扭_ σ比嗤並[3,4-c]異喹啉-u-二胺； 3-(5_(3,5-二氯吡啶_4_基胺基）小羥基_8,8_二甲基 -6,7,8,9-四氫-3H-吼唑並[3,4-c]異喹啉·3·基磺醯基⑼算二甲基苯曱醯胺； ’ ~ 5-(3,5-二氯吼啶-4-基胺基)-3-(3-甲氡基笨甲基)_8,8_ 二曱基-6,7,8,9-四氫-3H-吡唑並[3,4-c]異喹琳_ι_醇； 5-(3,5-二氯吼啶_4-基胺基)-3,8,8-三曱基_6,7,8,9_四氫坐並[3,4_c]異喧淋-1-醇； 3-((5-(3,5-一氣π比淀-4-基胺基)_ι_經基_8,8_二甲基 -6,7,8,9-四氫·3Η-π比峻並[3,4-c]異啥琳_3-基）甲基)苯曱酸甲酯； 13 201031663 3-((5-(3,5-二氣α比啶·4-基胺基）+羥基_8，卜二甲基 •6,7,8,9-四氳·3Η-吡唑並[3,4-c]異喹啉-3-基）甲基)苯甲酸；、 5-(3,5-二氯吡啶_4_基胺基)-8,8-二曱基_3_(吡啶-3-基甲基)-6,7,8,9-四氫—3H-吡唑並[3,4-c]異啥琳醇； 2- (5-(3,5-二氯η比咬·4-基胺基）小羥基_8,8_二甲基 -6,7,8,9-四氫-3Η-吡唑並[3,4-c]異喹啉-3-基）乙醯胺； 3- ((5-(3,5-二氣〇比咬_4_基胺基）-i_經基_8,8_二甲基 -6,7,8,9-四氫-3H-吡唑並[3,4-c]異喹啉_3_基）曱基）苯甲醯 @ 胺； 4- ((5-(3,5-二氣咐^_4·基胺基；羥基_8,8_二甲基 -6,7,8,9-四氫-3H-吡唑並[3,4-c]異喹琳-3-基）曱基)苯甲酸甲酯； 4-((5-(3,5-一乳0比唆-4-基胺基）小經基_8,8_二甲基 -6,7,8,9-四氳-3H-吡唑並[3,4-c]異喹啉-3-基）甲基)苯曱酸； 3- ((5-(3,5_二氣吼α定_4_基胺基）」_羥基_8,8_二甲基 -6,7,8,9-四風比峻並[3,4-c]異啥琳-3-基）甲基)苯甲腈；201031663 In the invention, the other is a better-supplemented towel, r1 is a slight or an amine group; R represents a hydrogen atom 'methyl group, a -CH2CONH2 group, a fluorene-3-yl fluorenyl group, and the case is - a benzyl T group substituted by a methoxy group, a methoxy group, an amine carbaryl group, and a cyclyl group (4), optionally selected by a group consisting of a cyano group and an amine mercapto group. Substituent substituted 3-phenylpropyl '3 for mercapto) propyl or 3-mercaptomethylamine decyl); and R3 represents 3,5-digas alpha ratio _4_ group. Specific individual compounds of the invention comprise: 5_(3,5-dichloropyridinylamino)-indolediyl-6,7,8,9,hydro-3Η·-biwa[3,4- c]isoquinoline small alcohol; N -(3,5-dichloropyridine_4_yl)_8,8-dimercapto_6,7,8,9_four gas_twist_σ ratio 嗤[3 , 4-c]isoquinoline-u-diamine; 3-(5-(3,5-dichloropyridin-4-ylamino)hydroxyl-8,8-dimethyl-6,7,8, 9-tetrahydro-3H-carbazolo[3,4-c]isoquinoline·3·ylsulfonyl (9) dimethyl benzoguanamine; ' ~ 5-(3,5-dichloroacridine -4-ylamino)-3-(3-carbamimidylmethyl)_8,8-dimercapto-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c] Isoquinoline_ι_alcohol; 5-(3,5-dichloroacridin-4-ylamino)-3,8,8-tridecyl_6,7,8,9_tetrahydroanthracene[ 3,4_c]isoindolin-1-ol; 3-((5-(3,5-one gas π-precipitate-4-ylamino)_ι_yl group_8,8-dimethyl-6,7 ,8,9-tetrahydro·3Η-π ratio [3,4-c]isoindene _3-yl)methyl)benzoic acid methyl ester; 13 201031663 3-((5-(3,5) -diqi α-pyridyl 4-ylamino)+hydroxy-8,dimethyl•6,7,8,9-tetrazole·3Η-pyrazolo[3,4-c]isoquinoline- 3-yl)methyl)benzoic acid; 5-(3,5-dichloropyridyl-4-ylamino)-8,8-diindenyl-3-(3-pyridin-3-yl) 6,6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoindolinol; 2-(5-(3,5-dichloro-n-biti-4-yl Amino) small hydroxy-8,8-dimethyl-6,7,8,9-tetrahydro-3indole-pyrazolo[3,4-c]isoquinolin-3-yl)acetamide; - ((5-(3,5-two gas 〇 than bite _4_ ylamino)-i_ via _8,8-dimethyl-6,7,8,9-tetrahydro-3H-pyridyl Zoxao[3,4-c]isoquinoline-3-yl)indenyl)benzamide@amine; 4-((5-(3,5-di-gas 咐^_4.ylamino); hydroxy_8 ,8-dimethyl-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-3-yl)indenyl)benzoic acid methyl ester; 4-(( 5-(3,5-monomilose 0 to indol-4-ylamino) sulfonic acid _8,8-dimethyl-6,7,8,9-tetraindole-3H-pyrazolo[3, 4-c]isoquinolin-3-yl)methyl)benzoic acid; 3-((5-(3,5_digas 吼α定_4_ylamino))_hydroxy_8,8_ Dimethyl-6,7,8,9-tetra wind ratio and [3,4-c]isoindol-3-yl)methyl)benzonitrile;

4- ((5-(3,5-二氯吡啶_4·基胺基）+羥基_8,8_二甲基 G -6,7,8,9-四氫-3H-吼唑並[3,4_c]異喹啉_3·基）f基）苯甲^ 胺； 5- (3,5-二氯吡啶斗基胺基)-8,8-二甲基_3_(3·(ν_嗎啉基)丙基)-6,7,8,9-四氫-3Η-吼唑並[3,4-c]異喹琳醇； 3-(3-(5-(3,5-二氯吼啶_4_基胺基)小羥基_8,8_二甲基 -6,7,8,9-四氳-3H-吡唑並[3,4-c]異喹啉基)丙基)苯甲腈； 3-(3-(5-(3,5-二氯吡啶_4_基胺基經基_8,8_二甲基 14 201031663 -6,7,8,9-四氫-3H-吡唑並[3,4_c]異喹啉_3_基）丙基）苯甲醯胺。備受關注的是： 5-(3,5-二氯吡啶冰基胺基)_8,8_二甲基_6,7,8,9_四 -3Η-α比0坐並[3,4-c]異啥淋小醇；里 3-((5-(3,5-二氯吡啶冰基胺基)-1-羥基-8,8-二甲基4-((5-(3,5-Dichloropyridine-4amino)}hydroxy-8,8-dimethyl G-6,7,8,9-tetrahydro-3H-indazole[ 3,4_c]isoquinoline _3·yl)f-yl)benzamide; 5-(3,5-dichloropyridinylamino)-8,8-dimethyl-3-3_(3·(ν _ morpholinyl)propyl)-6,7,8,9-tetrahydro-3indole-oxazolo[3,4-c]isoquinolinol; 3-(3-(5-(3,5-) Dichloroacridine_4_ylamino)hydroxyl-8,8-dimethyl-6,7,8,9-tetraindole-3H-pyrazolo[3,4-c]isoquinolinyl) Propyl)benzonitrile; 3-(3-(5-(3,5-dichloropyridine-4-ylamino)-based -8,8-dimethyl 14 201031663 -6,7,8,9- Tetrahydro-3H-pyrazolo[3,4_c]isoquinolin-3-yl)propyl)benzamide. Of great interest: 5-(3,5-dichloropyridyl amylamino) _8,8_Dimethyl_6,7,8,9_tetra-3Η-α is 0 and [3,4-c]isoindole small alcohol; 3-((5-(3,5-) Dichloropyridyl amylamino)-1-hydroxy-8,8-dimethyl

_6,7,8,9-四氫_3H-n比峻並p，4_c]異喹琳各基）甲基)苯甲酸甲醋， 3-((5-(3,5-二氯吡啶斗基胺基）小羥基_8,8_二甲基 _6,7,8,9_四氬-3心比峻並[3,4_c]異啥琳基)甲基)笨甲酸^ 3-((5_(3,5-二氣吡啶斗基胺基)]_羥基_8,8_二甲基二氣吡啶_4_基胺基）小羥基·8,8_二甲 -6,7,8,9-四氫-肌吡唑並[3,4_e]異喹啉I基）甲基)苯甲酸 3-((5-(3,5-二氯吡啶_4·基胺基）心羥基_8,8_二甲 -6,7,8,9-四氳-瓜対並[3,4_c]異啥琳_3_基)τ基) 3_(3-(5-(3,5-二氯吡啶斗基胺基H_幾基_8,8·二^ 胺。、根據另-實施例，本發明涵蓋醫藥組合物，或多種如上文所述之式⑴化合物與醫藥學上可接受之釋劑或載劑的混合物。在又-實施例中，本發明涵蓋一種組合產物 15 201031663 同時、分開或依序用於治療人體或動物體之（i)如上文所述之式（I)化合物，以及（ϋ)另一選自以下之化合物：（昀腎上腺素激導性促效劑、（b)抗膽鹼劑（諸如m3蕈毒驗受體之拮抗劑）、（c)消炎劑、（d)抗過敏劑、（e)免疫抑制劑以及（f)抗感染劑。 & 〇根據又一實施例’本發明是針對如上文所述之式（工）化合物’其用於治療易藉由抑制磷酸二酯酶4來改善之病理學病狀或疾病；以及本發明之化合物的用途，其用於製造供治療或預防易藉由抑制磷酸二酯酶4來改善之病理學，狀或疾病的藥劑。其是使用式（1)化合物製造用於治^ ，預防如下病症之藥劑的較佳實施例，所述病症為哮喘、 k性阻塞性肺病、過敏性鼻炎、類風濕性關節炎、多發性硬化症、異位性皮膚炎、牛皮癬、發炎性腸病。根據又一實施例，本發明涵蓋一種治療罹患易藉由抑文—酯酶4來改善之病理學病狀或疾病之個體的方 ''、，所述方法包括向所述個體投與有效量之如上文所述之化合物。在一較佳實施例中，所述方法是用於治療下病理學病狀或赫之個體，所翻狀或疾病為哮 = 性阻塞性肺病、過敏性鼻炎、類風濕性關節炎、多 ^硬化症、異位性皮膚炎、牛皮癬、發紐腸病。 =發明之化合物可藉由諸如以下流程中所說明之方。賴、溫度、壓力以及其他反應條件可易於由 -項技術者選擇。起始㈣是市售的或可易於由般熟S此項技術者使用已知方法來製備。對於下文所述 16 201031663 之所有流程以及化合物，R1以及R2如對於通式（1)化合物所述。_6,7,8,9-tetrahydro_3H-n ratio and p,4_c]isoquinoline)methyl)benzoic acid methyl vinegar, 3-((5-(3,5-dichloropyridine) Amino group) small hydroxyl group _8,8-dimethyl_6,7,8,9_tetra argon-3 core ratio [3,4_c]isoindolyl)methyl) benzoic acid ^ 3-( (5_(3,5-dioxapyridylamino)]-hydroxy-8,8-dimethyldipyridyl-4-ylamino)hydroxyl-8,8-dimethyl-6,7, 8,9-Tetrahydro-musclepyrazolo[3,4_e]isoquinoline I-yl)methyl)benzoic acid 3-((5-(3,5-dichloropyridine-4-amino)aminol) _8,8_Dimethyl-6,7,8,9-tetrazole-cucurbitate[3,4_c]isoindene _3_yl)taki) 3_(3-(5-(3,5- Dichloropyridinylamino-H_monomethyl-8,8-diamine. According to another embodiment, the invention encompasses a pharmaceutical composition, or a plurality of compounds of formula (1) as described above and pharmaceutically acceptable A release agent or a mixture of carriers. In yet another embodiment, the invention encompasses a combination product 15 201031663 for simultaneous, separate or sequential use in the treatment of a human or animal body (i) Formula (I) as described above a compound, and (ϋ) another compound selected from the group consisting of: (昀 adrenergic agonist, (b) an anticholinergic agent (b) An antagonist such as an m3 sputum receptor, (c) an anti-inflammatory agent, (d) an anti-allergic agent, (e) an immunosuppressive agent, and (f) an anti-infective agent. & 〇 according to still another embodiment Is directed to a compound of the formula (as described above) for treating a pathological condition or disease which is easily ameliorated by inhibition of phosphodiesterase 4; and the use of a compound of the invention for the manufacture of a therapeutic Or a medicament for preventing a pathology, a disease or a disease which is easily ameliorated by inhibiting phosphodiesterase 4. It is a preferred embodiment for producing a medicament for treating and preventing a condition using the compound of the formula (1), The condition is asthma, k-obstructive pulmonary disease, allergic rhinitis, rheumatoid arthritis, multiple sclerosis, atopic dermatitis, psoriasis, inflammatory bowel disease. According to yet another embodiment, the present invention contemplates treating a condition A method of ameliorating a pathological condition or a disease of an individual by inhibiting the text - esterase 4, the method comprising administering to the individual an effective amount of a compound as described above. In an embodiment, the method is for treatment The pathological condition or the individual of Hehe, the swaying or disease is stagnation = sexual obstructive pulmonary disease, allergic rhinitis, rheumatoid arthritis, multiple sclerosis, atopic dermatitis, psoriasis, enteropathy The compound of the invention can be used, for example, as illustrated in the following schemes. The temperature, pressure, and other reaction conditions can be readily selected by the skilled person. The starting (four) is commercially available or can be readily cooked. The skilled artisan prepares using known methods. For all of the procedures and compounds of 16 201031663 described below, R1 and R2 are as described for the compound of formula (1).

通式（I)化合物可按照圖1中所示之合成流程來製備。圖1The compound of formula (I) can be prepared according to the synthetic scheme shown in Figure 1. figure 1

X IX VIII VIIX IX VIII VII

根據 R.E. Mewshaw，Z，1989, 30(29), 3753-6 或 H. Ohmori 等人，the 〇/ ί/zeAccording to R.E. Mewshaw, Z, 1989, 30(29), 3753-6 or H. Ohmori et al, the 〇/ ί/ze

Chemical Society, Chemical Communications, 1988, (13), 874-5所述之方法，使市售中間物x與乙二醯氯在二甲基甲醯胺（DMF)存在下反應，得到3-氯-5,5-二曱基環己-2-烯酮IX。如 F· Sondheimer 以及 W, Saul, Jowrwa/ 〇/ 17 201031663A method described in Chemical Society, Chemical Communications, 1988, (13), 874-5, which reacts a commercially available intermediate x with ethylene dichloride in the presence of dimethylformamide (DMF) to give 3-chloro- 5,5-Dimercaptocyclohex-2-enone IX. Such as F· Sondheimer and W, Saul, Jowrwa/ 〇/ 17 201031663

Chemistry ,1959, 37 ,1870-80 或 U. Ghatak 等人，theChemistry, 1959, 37, 1870-80 or U. Ghatak et al., the

Journal of the American Chemical Society ,1957, 79 , 4487-91所述’使用如鈀之催化劑，使中間物ix與氫氣於壓力下反應’得到3,3-二甲基環己酮VIII。隨後根據 D.L. Boger 以及 M.D. Mullican，J⑽〇/ Organic Chemistry ,1985, 50(11), 1904-11，使中間物 VIII與碳酸二曱酯在諸如氫化鈉之鹼存在下反應，得到 1，3-二羰基衍生物VII。吡啶衍生物VI可藉由如E. Wenkert等人， 1965, 37, 5461所述，於回流條件下，在氳氧化鉀存在下’用氰基乙醯胺使中間物VII環化來製備。相同參考文獻適用於藉由在密封管中於150-17CTC下在無溶劑之情況下與氧氣化磷反應來使VI轉化為1，6-二氯吼咬衍生物V。中間物V轉化為IV在溶劑（較佳為極性非質子性溶劑，諸如N，N-二曱基曱醯胺、二噁烷、丙酮或四氫呋喃）中’在強驗（諸如氫化納或第三丁醇鉀）存在下且於 °(：至150°C之溫度下進行。在R3_NH2反應物中，R3如前文所定義。 III之相應衍生物可使用濃硫酸來製備，得到所需最終中間物III，其不經進一步純化即可用於下一合成步驟中。如 E.G. Paronikyan 等人，the Pharmaceutical ChemistryAs described in Journal of the American Chemical Society, 1957, 79, 4487-91, using a catalyst such as palladium, the intermediate ix is reacted with hydrogen under pressure to give 3,3-dimethylcyclohexanone VIII. Subsequent reaction of intermediate VIII with dinonyl carbonate in the presence of a base such as sodium hydride according to DL Boger and MD Mullican, J (10) 〇 / Organic Chemistry, 1985, 50 (11), 1904-11, gives 1,3-two Carbonyl derivative VII. The pyridine derivative VI can be prepared by cyclizing the intermediate VII with cyanoacetamide under reflux conditions in the presence of potassium hydride as described in E. Wenkert et al., 1965, 37, 5461. The same reference applies to the conversion of VI to the 1,6-dichloroindole bite derivative V by reaction with oxygenated phosphorus in a sealed tube at 150-17 CTC without solvent. Conversion of intermediate V to IV in a solvent (preferably a polar aprotic solvent such as N,N-didecylguanamine, dioxane, acetone or tetrahydrofuran) in a strong test (such as sodium hydride or third) In the presence of potassium butoxide) and at ° (: to 150 ° C. In the R3_NH2 reactant, R3 is as defined above. The corresponding derivative of III can be prepared using concentrated sulfuric acid to obtain the desired final intermediate III, which can be used in the next synthesis step without further purification. For example, EG Paronikyan et al., the Pharmaceutical Chemistry

Journal (Khimiko-Farmatsevticheskii Zhurnal 之譯 35(】)，8-10關於類似化合物所述，在諸如丁醇之溶劑中， 201031663 於加熱條件下，《使HI環化，得到巾間物H。化合物I可藉由使U與R2X (其中r2如前文所定 it較佳為_素原子㈤、α或n，儘管私 ίΐ麵惡燒、丙酮或四氫吱喃）中，在強驗（諸如 ί度=:?丁_)存在下且於室溫至贿範圍内之在R1表示胺基之特定情況下，通式照圖2中所示之合錢鋒製備。物7按圖2Journal (Khimiko-Farmatsevticheskii Zhurnal translation 35 ()), 8-10, for a similar compound, in a solvent such as butanol, 201031663 under heating, "cycling HI to obtain the towel H. Compound I By making U and R2X (where r2 is preferred as _ prime atom (five), alpha or n, although privately, it is badly burned, acetone or tetrahydrofuran), in the strong test (such as ί degree = In the specific case where R1 represents an amine group in the presence and at room temperature to bribe, the formula is prepared according to the combination of the money shown in Figure 2.

ia 式（la )化合物可藉由按照如E G Par〇ni 2TT1 一y Jo:rnal (Khumko-Farmatsevtichda zhumcd 之譯文)，彻、 8-10關於齡化合物所述之相同程序，在如丁醇之溶劑中，於加熱條件下，用肼使中間物IV環化來製備。在轉化在上文所述之方法的條件下易於發生化學反應或與所述方法不相容之細的情訂，可根據標準規範使用备知保護基’例如參見τ w Greene以及p g m篇故 ’Protective Groups in 0rganic Chemistry，，第 3 版，允汕 19 201031663Ia The compound of formula (la) can be used in a solvent such as butanol by the same procedure as described for EG Par〇ni 2TT1 - y Jo:rnal (translation of Khumko-Farmatsevtichda zhumcd), 8-10 for aged compounds It is prepared by cyclizing the intermediate IV with hydrazine under heating. In the case of conversion to the conditions described above, the chemical reaction is liable to occur or is incompatible with the method, and the protective group can be used according to standard specifications 'see, for example, τ w Greene and pgm articles' Protective Groups in 0rganic Chemistry,, 3rd edition, permissible 19 201031663

Wiley & Sons (1999)。在此情況下，脫除保護基可根據俨準規範（參見上述參考文獻）在最後一步中進行，從而到最終式I化合物。寸由式（V)表示之本發明之化合物的醫藥學上可接受之鹽可為酸加成鹽或鹼加成鹽。酸加成鹽之實例包含無機酸加成鹽’例如鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硫酸鹽、硝酸鹽、磷酸鹽；以及有機酸加成鹽，例如乙酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、擰檬酸鹽、乙二酸鹽、丁二酸鹽、酒石酸鹽、蘋果酸鹽、杏仁酸鹽、甲確酸鹽以及對甲苯磺酸鹽。鹼加成鹽之實例包含無機鹽，例如鈉、鉀、約以及銨鹽；以及有機驗金屬鹽’例如乙二胺、乙醇胺、二伸烷基乙醇胺、三乙醇胺以及鹼性胺基酸鹽。由上述式（I)表示之本發明之化合物可包含對映異構體’此視其不對稱性或非對映異構體而定。單一異構體以及異構體混合物屬於本發明之範缚内。【實施方式】本發明之化合物以及其中所用之中間物的合成是由以下實例（1-17)(包含製備實例（製備丨至12))來說明，所述實例不以任何方式限制本發明之範疇。在Varian Gemini 200光譜儀上記錄咕核磁共振光譜 (H Nuclear Magnetic Resonance Spectra )。在使用ESI電離之Micromass ZMD質譜儀上記錄低解析度質譜（Low Resolution Mass Spectra ) ( m/z )。 201031663 使用Perkin Elmer DSC-7設傷記錄熔點。使用震備有對稱C18(2.lxl0亳米，3、.5mM)管柱之 =⑽細系統獲得層析分離物。移動相為甲酸⑽毫 ^、氣⑷毫升)、甲醇（毫升）以及乙腈⑼。毫升）⑻’^及甲酸（0·46毫升）、氨（〇115毫升）以及水（1000毫升）（Α).最初在20分鐘内是〇%至95%Β，Wiley & Sons (1999). In this case, the removal of the protecting group can be carried out in the final step according to the standard specification (see above reference) to the final compound of formula I. The pharmaceutically acceptable salt of the compound of the present invention represented by the formula (V) may be an acid addition salt or a base addition salt. Examples of the acid addition salt include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; and organic acid addition salts such as acetate, cis. Oleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, formate and p-toluenesulfonate. Examples of the base addition salt include inorganic salts such as sodium, potassium, about, and ammonium salts; and organic metal salts such as ethylenediamine, ethanolamine, dialkylethanolamine, triethanolamine, and basic amino acid salts. The compound of the present invention represented by the above formula (I) may contain an enantiomer, depending on its asymmetry or diastereomer. Single isomers as well as isomer mixtures are within the scope of the invention. [Embodiment] The synthesis of the compound of the present invention and the intermediate used therein is illustrated by the following Examples (1-17) (including Preparation Examples (Preparation of oxime to 12)), which does not limit the present invention in any way. category. H Nuclear Magnetic Resonance Spectra was recorded on a Varian Gemini 200 spectrometer. Low Resolution Mass Spectra (m/z) was recorded on a Micromass ZMD mass spectrometer using ESI ionization. 201031663 The melting point was recorded using Perkin Elmer DSC-7. The chromatographic isolate was obtained using a =(10) fine system with a symmetric C18 (2.lxl0 亳m, 3, .5 mM) column. The mobile phases were formic acid (10) mmol, gas (4) mL), methanol (ml) and acetonitrile (9). Milliliter) (8)'^ and formic acid (0.46 ml), ammonia (〇115 ml) and water (1000 ml) (Α). Initially 〇% to 95% 20 in 20 minutes,

且隨後4分鐘是95% Β。兩次注射之間的重新平衡時間為 5勿鐘。流速為〇.4鼋升/分鐘。注射體積為5微升。在 ηΜ下收集二極體陣列層析圖。製備實例製備1And then 4 minutes is 95% Β. The rebalancing time between the two injections was 5 minutes. The flow rate is 〇4鼋L/min. The injection volume was 5 microliters. The diode array chromatogram was collected under ηΜ. Preparation example Preparation 1

3-氣-5,5-二甲基環己_2_烯酮 ❹ 將5,5-二曱基環己-ΐ，3-二酮（2〇公克’ 0.14莫耳）懸浮於甲苯（75毫升）中。添加5滴PMF後’逐滴添加乙二醯氯（15.75毫升，0.18莫耳）。將此混合物加熱至85 ΐ歷時2小時。於減壓下蒸發溶劑後，獲得呈油狀物之所 t最終化合物（24公克）且其不經進〆步純化即可用於以下步驟。 iH NMR (200 MHz，氯仿δ ^09 (s，6 H) 2.25 (s, 2 Η) 2.56 (s, 2 Η) 6.22 (s, 1 Η) 製備2 2010316633-Gas-5,5-dimethylcyclohexane-2-enone oxime 5,5-Dimercaptocyclohexan-indole-3-butanone (2 〇g '0.14 mol) suspended in toluene (75 In milliliters). After adding 5 drops of PMF, ethyl ruthenium chloride (15.75 ml, 0.18 mol) was added dropwise. The mixture was heated to 85 ΐ for 2 hours. After evaporating the solvent under reduced pressure, the title compound (24 g) was obtained as an oil. iH NMR (200 MHz, chloroform δ ^09 (s, 6 H) 2.25 (s, 2 Η) 2.56 (s, 2 Η) 6.22 (s, 1 Η) Preparation 2 201031663

3,3-二甲基環己酮將3-氯-5,5-二曱基環己-2-烯酮（24公克’ 0.15莫耳，參見製備1)懸浮於戊烷（200毫升）中。添加三乙胺（26 毫升，0.19莫耳）以及鈀（1.5公克Pd/C 10%，0.01莫耳）。在18小時内於35磅/平方吋下使反應混合物氫化。照常處理後，藉由蒸餾純化後，獲得11.8公克最終產物。 ❿ 4 NMR (200 MHz,氣仿δ ppm 0.88 - 0.96 (m，6 H) 1.42 - 1.59 (m, 2 H) 1.73 - 1.94 (m, 2 H) 2.10 (s, 2 H) 2.22 (t, /=7.03 Hz, 2 H) 製備33,3-Dimethylcyclohexanone 3-Chloro-5,5-dimercaptocyclohex-2-enone (24 g '0.15 mol, see Preparation 1) was suspended in pentane (200 mL) . Triethylamine (26 mL, 0.19 mol) and palladium (1.5 g Pd/C 10%, 0.01 mol) were added. The reaction mixture was hydrogenated at 35 psig over 18 hours. After the usual treatment, after purification by distillation, 11.8 g of the final product was obtained. ❿ 4 NMR (200 MHz, gas δ δ ppm 0.88 - 0.96 (m, 6 H) 1.42 - 1.59 (m, 2 H) 1.73 - 1.94 (m, 2 H) 2.10 (s, 2 H) 2.22 (t, / =7.03 Hz, 2 H) Preparation 3

X XX X

4,4-二甲基-2_側氧基環己烷曱酸曱酯向氫化鈉（7.7公克，0.19莫耳）於THF (200毫升）中之混合物中添加碳酸二甲酯（39.5毫升，0.47莫耳）且加熱至回流。逐滴添加3,3-二曱基環己酮（11.8公克，〇.〇9 莫耳，參見製備2)之THF (100毫升）溶液且在擾拌下加熱2小時。冷卻直至室溫後，將反應混合物傾倒於氯化銨（300毫升）之飽和溶液上且用***萃取。照常處理後，獲得17.9公克呈油狀物之最終化合物。 4 NMR (200 MHz,氯仿δ ppm 0.87 - 1.00 (m, 6 η) 22 201031663 1.33 - 1.47 (m, 2 Η) 1.57 - 1.75 (m, 1 Η) 2.04 (s, 2 Η) 2.15 -2.30 (m, 2 Η) 3.72 - 3.78 (m, 3 Η) 製備4Add dimethyl carbonate (39.5 ml, to a mixture of sodium hydride (7.7 g, 0.19 mol) in THF (200 mL). 0.47 moles) and heated to reflux. A solution of 3,3-dimercaptocyclohexanone (11.8 g, 〇. 9 mol, see Preparation 2) in THF (100 mL) was added dropwise and heated with stirring for 2 h. After cooling to room temperature, the reaction mixture was poured with EtOAc EtOAc m. After the usual treatment, 17.9 g of the final compound was obtained as an oil. 4 NMR (200 MHz, chloroform δ ppm 0.87 - 1.00 (m, 6 η) 22 201031663 1.33 - 1.47 (m, 2 Η) 1.57 - 1.75 (m, 1 Η) 2.04 (s, 2 Η) 2.15 -2.30 (m , 2 Η) 3.72 - 3.78 (m, 3 Η) Preparation 4

+ 、。人b 1,3-二羥基-6,6-二甲基-5,6,7,8-四氫異喹啉-4-甲腈+ ,. Human b 1,3-dihydroxy-6,6-dimethyl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile

將4,4-二曱基-2-侧氧基環己烷曱酸甲酯（5.7公克， 30.9毫莫耳，參見製備3)溶解於甲醇（25毫升）中且添加氰基乙醯胺（2.6公克，30.9毫莫耳）。逐滴添加氳氧化鉀（1.8公克，32.4毫莫耳）之甲醇（7毫升）溶液。於室溫下攪拌混合物30分鐘且回流隔夜。一旦於室溫下後，過濾所形成之固體且用曱醇沖洗。將此固體懸浮於水中且用濃鹽酸酸化。於90°C下攪拌3小時後，過濾固體且用水洗滌。獲得2.73公克最終化合物。 lU NMR (200 MHz, DMSO-i/6) δ ppm 0.93 (s, 6 Η) 1.45 (t, J=6.44 Hz, 2 H) 2.28 - 2.41 (m, 4 H) 製備5Methyl 4,4-dimercapto-2-oxocyclohexanecarboxylate (5.7 g, 30.9 mmol, see Preparation 3) was dissolved in methanol (25 mL) and cyanoacetamide was added ( 2.6 grams, 30.9 millimoles). A solution of potassium cesium hydroxide (1.8 g, 32.4 mmol) in methanol (7 mL) was added dropwise. The mixture was stirred at room temperature for 30 minutes and refluxed overnight. Once at room temperature, the solid formed was filtered and rinsed with methanol. This solid was suspended in water and acidified with concentrated hydrochloric acid. After stirring at 90 ° C for 3 hours, the solid was filtered and washed with water. 2.73 grams of the final compound was obtained. lU NMR (200 MHz, DMSO-i/6) δ ppm 0.93 (s, 6 Η) 1.45 (t, J = 6.44 Hz, 2 H) 2.28 - 2.41 (m, 4 H) Preparation 5

1，3-二氣-6,6-二甲基-5,6,7,8-四氮異喧嚇甲赌在密封容器中於170°C下隔夜加熱1，3-二羥基-6,6-二曱基-5,6,7,8-四氳異喹啉-4-甲腈（2.73公克，12.51毫莫耳， 23 201031663 參見製備4)以及氧氣化填（8毫升，12.5毫莫耳）。一旦於室溫下後，將此混合物傾倒於2 N NaOH/冰上，用乙酸乙酯萃取’經由硫酸鎮乾燥且於減壓下蒸發。獲得公克呈固體狀之最終產物。 H NMR (400 MHz,氣仿 4 § ppm 1,〇3 (s，6 H) 1.67 (t, 6.85 Hz, 2 H) 2.74 (s, 2 H) 2.78 (t, J=6.65 Hz, 2 H) 製備6 ，1,3-dieso-6,6-dimethyl-5,6,7,8-tetraazaisoindole scared to heat 1,3-dihydroxy-6 overnight at 170 ° C in a sealed container. 6-Dimercapto-5,6,7,8-tetradecyiquinoline-4-carbonitrile (2.73 g, 12.51 mmol, 23 201031663 see Preparation 4) and oxygenated fill (8 ml, 12.5 mmol) ear). Once at room temperature, the mixture was poured onto 2 N NaOH / ice and extracted with ethyl acetate. The final product was obtained in the form of a solid. H NMR (400 MHz, MV 4 § ppm 1, 〇 3 (s, 6 H) 1.67 (t, 6.85 Hz, 2 H) 2.74 (s, 2 H) 2.78 (t, J = 6.65 Hz, 2 H) Preparation 6,

二甲基-5,6,7,8- 3-氣-1-(3,5-二氣《比啶-4-基胺基)_6,6_ 二四氫異喹啉-4-甲腈將1，3-一氣-6,6-二曱基_5,6,7,8_四氫異喹啉甲浐 (2.0公克，7.84毫莫耳，參見製備5)、3,5_二氣財冰^ (1.5公克，9.4毫莫耳）、第三丁醇鉀（176公克，ΐ5 7 莫耳）、Pd2(dba)3 (72毫克，0.08毫莫耳）以及氣化雙(2,6-二異丙基苯基)咪唑鏽（67毫克，〇16毫莫浮於二魏（3G毫升）巾且用氬氣淨化纽。於跡^ 加熱2小時後’將反應混合物傾倒於水上且用乙酸乙取。用2NHC1酸化殘餘水相且用乙酸乙醋萃取。照^ 理後’藉由急驟層析，用二氯甲烧/甲醇98:2溶離== 粗殘餘物且分離得到1.23公克最終產物。產率=41%，、 NMR (200 MHz，氣仿，鹏 i°。 201031663 *7=6.6 Hz，2 Η) 2.6 (t，J=6.6 Hz，2 Η) 2.7 (s，2 Η) 6.4 (s，1 Η) 8.5 (s, 2 H) 製備7Dimethyl-5,6,7,3- 3- gas-1-(3,5-digas "pyridin-4-ylamino)_6,6-ditetrahydroisoquinoline-4-carbonitrile 1,3-一气-6,6-dimercapto_5,6,7,8-tetrahydroisoquinoline formazan (2.0 g, 7.84 mmol, see Preparation 5), 3,5_two gas Ice ^ (1.5 grams, 9.4 millimoles), potassium t-butoxide (176 grams, ΐ 5 7 moles), Pd2 (dba) 3 (72 mg, 0.08 millimoles), and gasification doubles (2,6-) Diisopropylphenyl)imidazole rust (67 mg, 〇16 mM floated in diwei (3G ML) towel and fluoresced with argon. After heating for 2 hours at the traces ^ poured the reaction mixture onto water and used acetic acid Take the residue. Acidify the residual aqueous phase with 2NHC1 and extract with ethyl acetate. After purification, by flash chromatography, dissolve with methylene chloride/methanol 98:2 == crude residue and isolate 1.23 g of final product Yield = 41%, NMR (200 MHz, gas simulation, Peng i°. 201031663 *7 = 6.6 Hz, 2 Η) 2.6 (t, J = 6.6 Hz, 2 Η) 2.7 (s, 2 Η) 6.4 (s,1 Η) 8.5 (s, 2 H) Preparation 7

❹ 3-氣-1-(3,5-二氣°比啶-4-基胺基)_6,6_二甲基 _5,6,7,8_ 四氫異喹啉-4-甲醢胺將3-氯-l-(3,5-二氯咐•啶-4-基胺基）_6,6·二曱基 -5,6,7,8-四氫異喹啉-4-甲腈（1〇〇亳克，〇26毫莫耳，參見製備6)懸浮於濃硫酸（1毫升）中且於6(rc下加熱混合❹ 3-气-1-(3,5-dioxabipyridin-4-ylamino)_6,6-dimethyl-5,6,7,8-tetrahydroisoquinoline-4-carboxamide 3-Chloro-l-(3,5-dichloroindole-4-ylamino)-6,6-didecyl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (1 g, 〇26 mmol, see Preparation 6) suspended in concentrated sulfuric acid (1 ml) and heated at 6 (rc)

物。一旦反應結束後，將混合物傾倒於冰上，用氨鹼化用氣仿萃取。照常處理後，獲得62毫克呈白需最終產物，其不經進一步純化即可用於下體狀之所 HPLC/MS (I5分鐘）滯留時間：I%〜合成蚩綠。 LRMS: w/z 399 (M+) 製備8Things. Once the reaction was completed, the mixture was poured onto ice and extracted with an ammonia sulphonation using a gas mixture. After the usual treatment, 62 mg of the desired final product was obtained, which was used for the sub-forms without further purification. HPLC/MS (I5 min) retention time: I%~ Synthetic indigo. LRMS: w/z 399 (M+) Preparation 8

3-(二甲基胺甲醢基)苯小項醯氣將3_(氯磺醯基)苯甲醯氣（5公克，Μ 甲苯（5〇毫升）溶液冷卻至且在Μ分會9毫莫冬） Μ二甲胺之THF溶液(2〇 9毫升，41 8 ‘内，恭力二、耳）。__ 25 201031663 加結束後’於室溫下攪拌反應物隔夜。將反應混合物傾倒於水上，用水以及鹽水依次洗滌有機相，經由硫酸鎂乾燥，過濾且於減壓下蒸發溶劑。藉由急驟層析，用己烷/AcOEt 7:3溶離來純傾餘物，分離制2 8公克呈錄物之最終化合物。產率=550/。。 H NMR (200 MHz，氯仿4 δ. ppm 3.0 (s，3 H) 3.2 (s， 3 Η) 7.7 (m，1 Η) 7.8 (m, 1 Η) 8.1 (m，2 η) ’ 製備93-(dimethylaminomethionyl)benzene small xenon gas cooled 3_(chlorosulfonyl)benzhydrazide (5 g, Μ toluene (5 ml) solution to 9 min. Μ dimethylamine in THF solution (2 〇 9 ml, 41 8 ', Christine II, ear). __ 25 201031663 After the end of the addition, the reaction was stirred at room temperature overnight. The reaction mixture was poured onto water, and the organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The final compound was prepared by flash chromatography, eluting with hexane/AcOEt 7:3 to yield a pure residue. Yield = 550/. . H NMR (200 MHz, chloroform 4 δ. ppm 3.0 (s, 3 H) 3.2 (s, 3 Η) 7.7 (m, 1 Η) 7.8 (m, 1 Η) 8.1 (m, 2 η) ’ Preparation 9

4-溴甲基苯曱醯胺4-bromomethylphenylamine

將4_漠曱基苯曱酸（削毫克，〇 47毫莫耳）懸浮於乙酸乙酯中且添加亞硫醯氯（51微升，0.70暮替、 75 C下加熱此混合物20小時。接著將其冷卻至〇、、濃氨（56.4微升）並在20分鐘内攪拌。添加且，加由Celite®過濾。用乙酸乙酯萃取此水相，用/且接著經4_Mercaptobenzoic acid (milling milligrams, 〇47 mmol) was suspended in ethyl acetate and sulfite chloride (51 μl, 0.70 Torr, 75 ° C was used to heat the mixture for 20 hours. It was cooled to hydrazine, concentrated ammonia (56.4 μl) and stirred over 20 minutes. Add and filter with Celite®. Extract this aqueous phase with ethyl acetate, with / and then

以及鹽水洗滌，經由硫酸鎮乾燥，過渡且於減壓二$ 劑。獲得40毫克呈固體狀之最終產物。？、、、發溶 4.98 (m，2 W NMR (200 MHz, DMSO-木）δ ppm 4 68 Η) 7.38 - 7.71 (m, 2 Η) 7.78 - 8.16 (m, 2 Η) 製備10And brine washing, drying through sulfuric acid, transition and decompression. 40 mg of the final product was obtained as a solid. ? ,,, and soluble 4.98 (m, 2 W NMR (200 MHz, DMSO-wood) δ ppm 4 68 Η) 7.38 - 7.71 (m, 2 Η) 7.78 - 8.16 (m, 2 Η) Preparation 10

甲磺酸3-(N-嗎啉基)丙酯 26 201031663 及三毫公克，3·44毫莫耳）以毫升)中逐二耳)溶解於二氯甲烧(10 1甲二，（〇.40亳升，5.1?亳莫耳）之 ^ 於室溫下搜拌隔夜。照化即7用二=:?最終產物’其不經進-步純 Ο NMR (20〇 MHz, a^r-c〇 δ ppm 1.83 - 2 11 (m 2 H) 2·35 - 2.59 (m, 4 H) 3.03 (s, 3 H) 3 47 3 67 r o ^(^2H)4,7-^4(m,4H) (mj2H)3·67-3-(N-morpholinyl)propyl sulfonate 26 201031663 and three milligrams, 3.44 millimoles) in milliliters), dissolved in dichloromethane (10 1 alpha 2, (〇 .40亳升, 5.1?亳莫耳)^ Mix overnight at room temperature. Illumination is 7 with two =:? The final product 'It's not advanced - NMR (20〇MHz, a^rc 〇δ ppm 1.83 - 2 11 (m 2 H) 2·35 - 2.59 (m, 4 H) 3.03 (s, 3 H) 3 47 3 67 ro ^(^2H)4,7-^4(m,4H ) (mj2H)3·67-

3-(3-溴丙基)苯甲腈3-(3-bromopropyl)benzonitrile

腈（7毫二二—苯基膦（5.〇公克’ D·1毫莫耳）之乙填α溶解於乙猜（14毫升）中之 g添==乙腈(7毫升）中之3伽丙基)苯甲腈⑵ 至束時，將反應混合物加熱至乾。經k氧切，賴且將液相蒸發化油性殘餘物，獲得^=::(。9:1)溶離來純 2.84 MHZ，氯仿4 S PPm 2.〇G · 2.32 (m，2 H) (m，4 Ή) . HZ，2 Ή) 3.39 化片別 Hz，2 Η) 7‘29 · 7.70 27 201031663The nitrile (7 mM diphenyl-phenylphosphine (5. 〇克 ' D · 1 mmol) of B is dissolved in B guess (14 ml) of g = = acetonitrile (7 ml) of 3 gamma When propyl)benzonitrile (2) is applied to the bundle, the reaction mixture is heated to dryness. After k-oxygen cleavage, the liquid phase is evaporated to an oily residue to obtain ^=::(.9:1) dissolving to pure 2.84 MHZ, chloroform 4 S PPm 2.〇G · 2.32 (m, 2 H) ( m,4 Ή) . HZ,2 Ή) 3.39 片, Hz, 2 Η) 7'29 · 7.70 27 201031663

3_(3、溴丙基)苯甲醢胺 f 3-(3_漠丙基)苯甲腈（2公克，8 9 公克’3毫莫耳)溶解於甲醇拌::鐘==’17.8毫莫耳)。於= 醇⑶m碳酸卸05公克1〇8.5毫莫耳）之ϊ 升）/谷液且於室溫下攪拌隔夜。添加4〇毫升水接著於5°C下靜置此反應混合物片刻。過濾半固體且藉由急驟層析，用己烷/AcOEt2:l溶離來純化，分離得到〇./6 公克呈固體狀之最終產物。 H NMR (200 MHz, DMSO-i/6) δ ppm 1.96 - 2.24 (m, 2 H) 2.67 - 2.87 (m, 2 H) 3.52 (t, J=6.64 Hz, 2 H) 7.20 - 7.43 (m, 3 H) 7.63 - 7.76 (m, 2 H) 7.93 (s, 1 H) 實例13_(3, bromopropyl) benzamide f 3-(3_glypropyl)benzonitrile (2 g, 8 9 g '3 mmol) dissolved in methanol:: clock == '17.8 m Moore). = = Alcohol (3) m carbonic acid unloading 05 g 1 〇 8.5 mmoles) )) / gluten solution and stirred at room temperature overnight. 4 ml of water was added and the reaction mixture was allowed to stand at 5 ° C for a while. The semi-solid was filtered and purified by flash chromatography, eluting with hexane/AcOEt 2:1 to afford s. H NMR (200 MHz, DMSO-i/6) δ ppm 1.96 - 2.24 (m, 2 H) 2.67 - 2.87 (m, 2 H) 3.52 (t, J = 6.64 Hz, 2 H) 7.20 - 7.43 (m, 3 H) 7.63 - 7.76 (m, 2 H) 7.93 (s, 1 H) Example 1

❹ 5-(3,5-二氣吡啶-4-基胺基)-8,8_二曱基-6,7,8,9-西氫 •3H-吡唑並[3,4-c]異喹啉-1·醇將3-氯-1-(3,5-二氯吼啶-4-基胺基）-6,6-二曱基 _5,6,7,8·四氫異喹啉-4-曱醯胺（62毫克，0.16毫莫耳，參 28 201031663❹ 5-(3,5-Di-pyridin-4-ylamino)-8,8-dimercapto-6,7,8,9-west hydrogen•3H-pyrazolo[3,4-c] Isoquinoline-1·ol will be 3-chloro-1-(3,5-dichloroacridin-4-ylamino)-6,6-dimercapto-5,6,7,8·tetrahydroiso Quinoline-4-decylamine (62 mg, 0.16 mmol, gin 28 201031663

見製備7)溶解於丁醇（5毫升）中且添加單水合肼ο” 微升’ 3.1j毫莫耳）。隔夜加熱至赠後，再添加單水合肼（0.5毫升）且再次加熱隔夜。蒸發溶劑後，將殘餘物溶解於2NNa〇H中且用氯仿萃取。用2NHClt|7和水相且用氯仿萃取。照常處理後，藉由急驟層析，用DCM/Me〇H 95:5溶離來純化殘餘物，得到13毫克呈白色固體狀之最終產物。 ❹ NMR _ MHz, dmsoo δ ppm 丨〇〇 (s 1.64 (s, 2 H) 2.50 (Sj 2 H) 2.83 (s, 2 H) 8.27 (s, 1 H) 8.65 (s, 2, H) 實例2See Preparation 7) Dissolved in butanol (5 mL) and added with monohydrate 肼 ο” microliters 3.1 j mmol. After heating overnight, add monohydrate hydrate (0.5 mL) and heat again overnight. After evaporating the solvent, the residue was dissolved in EtOAc EtOAc (EtOAc)EtOAc. The residue was purified to give 13 mg (yield: s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, (s, 1 H) 8.65 (s, 2, H) Example 2

吼唾卿-e]異料_15_ΓΓ心，7,8,9·四細_ 將3j_H3,5_m4_基胺基⑹ 其 _5,6,7,8-四氫異喹啉甲腈（1〇〇毫克，〇土 ^傷6)溶解於乙醇（1毫升）中且添加單:肼⑵= 升，5.23毫莫耳）。隔夜加熱至 ^ (255微劑且將殘餘物懸浮於水中， ^厂、下蒸發溶乙醇再結晶。獲得％毫絲絲料从㈣洗條且自 Ή NMR (2〇〇 MHz, ^,ppmU(s6H)i8(t； 29 201031663 J=6.8 Hz, 2 H) 2.7 (m, 2 H) 2.9 (s, 2 H) 4.0 (s, 2 H) 6.4 (s, 1 H) 8.5 (s, 2 H) 8.9 (s, 1 H) 實例3吼吼卿-e] Heterogenous _15_ΓΓ心,7,8,9·四细_ Will 3j_H3,5_m4_ylamino (6) Its _5,6,7,8-tetrahydroisoquinoline carbonitrile (1〇〇mg, 〇土^伤6) Dissolved in ethanol (1 ml) and added a single: 肼 (2) = liter, 5.23 millimoles). Heated to ^ (255 micro-agents overnight) and suspended the residue in water, then re-crystallized by evaporation of ethanol in the factory. Obtained % millifilament from the (iv) strip and self-enthalpy NMR (2 〇〇 MHz, ^, ppmU ( s6H)i8(t; 29 201031663 J=6.8 Hz, 2 H) 2.7 (m, 2 H) 2.9 (s, 2 H) 4.0 (s, 2 H) 6.4 (s, 1 H) 8.5 (s, 2 H) ) 8.9 (s, 1 H) Example 3

3-(5-(3,5-二氣吼啶-4-基胺基）-1-羥基_8,8-二甲基 -6,7,8,9-四氫-3H-»比唑並[3,4-c]異喹啉-3-基磺醯基)-N，N-二曱基苯曱醯胺3-(5-(3,5-dioxacridin-4-ylamino)-1-hydroxy-8,8-dimethyl-6,7,8,9-tetrahydro-3H-»bazole And [3,4-c]isoquinolin-3-ylsulfonyl)-N,N-dimercaptobenzamide

將5-(3,5_二氯吼啶-4-基胺基)-8,8-二甲基-6,7,8,9-四氫 -3H-吡唑並[3,4-c]異喹啉-1-醇（50毫克，0.13毫莫耳，參見實例1)溶解於氣仿（2亳升）中。添加三乙胺（20微升，0.14毫莫耳）以及3_(二曱基胺甲醯基)苯小續醯氯（36 毫克’ 0.15毫莫耳，參見製備8)。於室溫下攪拌反應混合物3小時。照常處理後，藉由急驟層析，用己烷/Ac〇Et 3:7 溶離來純化殘餘物。獲得1〇毫克最終產物。 HPLC/MS (15分鐘）滯留時間：8.67分鐘 LRMS: m/z 實例45-(3,5-Dichloroacridin-4-ylamino)-8,8-dimethyl-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c Isoquinolin-1-ol (50 mg, 0.13 mmol, see Example 1) was dissolved in a gas (2 liter). Triethylamine (20 microliters, 0.14 millimoles) and 3-(dimethylmercaptomethyl) benzoquinone chloride (36 mg ' 0.15 millimoles, see Preparation 8) were added. The reaction mixture was stirred at room temperature for 3 hours. After usual treatment, the residue was purified by flash chromatography eluting with hexane/EtOAc EtOAc. One milligram of final product was obtained. HPLC/MS (15 min) retention time: 8.67 min LRMS: m/z Example 4

589 (M+);1嘗589 (M+); 1 taste

5-(3,5_二氣吼啶_4_基胺基甲氧基苯甲基)_8,8_ 30 201031663 二甲基-6,7,8,9-四氫-311-°比唑並[3,4-c]異喹琳小醇將5-(3,5-二氯吡啶_4-基胺基)_8,8-二甲基_6,7,8,9-四氫 ❹ -3H-吼嗤並[3,4-C]異喹啉小醇（5〇毫克，〇13亳莫耳，參見實例1)溶解於DMF (2毫升）中且添加氫化鈉（6〇% 己烧溶液，6.5毫克，0.18毫莫耳）。於氮氣下於室溫下攪拌此混合物10分鐘。接著添加溶解於DMF (丨毫升）中之3-曱氧基苄基氯（25毫克，0.16毫莫耳）且於室温下攪拌混合物隔夜。用水稀釋反應混合物後，固體沈澱，過濾且自乙醇再結晶’得到4毫克最終化合物。 HPLC/MS (15分鐘）滯留時間：9.99分鐘 LRMS: m/z 498 (M+) 實例55-(3,5-dioxacridine_4_ylaminomethoxybenzyl)_8,8_ 30 201031663 Dimethyl-6,7,8,9-tetrahydro-311-° azole [3,4-c]isoquinolinol will be 5-(3,5-dichloropyridin-4-ylamino)_8,8-dimethyl-6,7,8,9-tetrahydroanthraceine - 3H-indolo[3,4-C]isoquinoline small alcohol (5 mg, 〇13亳 mol, see Example 1) was dissolved in DMF (2 mL) and sodium hydride (6 〇% hexane) was added. Solution, 6.5 mg, 0.18 mmol. The mixture was stirred at room temperature for 10 minutes under nitrogen. Next, 3-decyloxybenzyl chloride (25 mg, 0.16 mmol) dissolved in DMF (EtOAc) was added and the mixture was stirred overnight at room temperature. After diluting the reaction mixture with water, the solid was precipitated, filtered and recrystallized from ethanol to give 4 mg of the final compound. HPLC/MS (15 min) retention time: 9.99 min LRMS: m/z 498 (M+) Example 5

5-(3,5-二氣》比咬冬基胺基)_3,8,8_三甲基_6,7,8,9_四氫 -3H-吼唑並[3,4-c]異喹啉小醇將5-(3,5-一氣〇比咬_4_基胺基)·8,8_二曱基_6,7,8,9-四氮 -3Η-吡唑並[3,4-c]異喹啉_1·醇（50毫克，〇.13毫莫耳，參見實例1)溶解於DMF (1.5毫升）中且於氮氣下添加氫化鈉（60%己烷溶液，6.5毫克，0.16毫莫耳）。授拌1〇分鐘後’添加碘曱烷（10微升，0.16毫莫耳）之dMF (〇 5 毫升）溶液且於室溫下攪拌混合物隔夜。照常處理後，藉 31 201031663 由層析來純化反應混合物，得到14毫克最終產物。 HPLC/MS (15分鐘）滯留時間：7.93 LRMS: m/z 392 (M+) 實例65-(3,5-digas) ratio _3,8,8-trimethyl_6,7,8,9-tetrahydro-3H-carbazolo[3,4-c] Isoquinoline small alcohol will be 5-(3,5-one gas enthalpy than _4_ylamino)·8,8-dimercapto-6,7,8,9-tetraaza-3Η-pyrazolo[ 3,4-c]isoquinoline-1-ol (50 mg, 〇.13 mmol, see Example 1) was dissolved in DMF (1.5 mL) and sodium hydride (60% hexanes. 6.5 mg, 0.16 mmol. After 1 min of stirring, a solution of iodomane (10 μl, 0.16 mmol) in dMF (5 mL) was added and the mixture was stirred at room temperature overnight. After treatment as usual, the reaction mixture was purified by chromatography from 31 201031663 to give 14 mg of the final product. HPLC/MS (15 min) residence time: 7.93 LRMS: m/z 392 (M+) Example 6

3-((5-(3,5-二氣吡啶-4-基胺基)-1-羥基-8,8-二甲基 _6,7,8,9_四氫-3H-吡唑並[3,4-c】異喹啉-3-基）曱基）苯甲酸甲酯根據實例4中所述之方法，使實例1之標題化合物 (100毫克，0.26毫莫耳）與3-(溴曱基)苯甲酸曱酯（73毫克，0.32毫莫耳）反應，得到97毫克（63%)標題化合物。 HPLC/MS ( 15分鐘）滯留時間8.87分鐘。 LRMS: miz 595 (M+) 實例73-((5-(3,5-dioxapyridin-4-ylamino)-1-hydroxy-8,8-dimethyl-6,7,8,9-tetrahydro-3H-pyrazole [3,4-c]Isoquinolin-3-yl)indenyl)benzoic acid methyl ester The title compound of Example 1 (100 mg, 0.26 mmol) and 3- Reaction with bromomethyl)benzoate (73 mg, 0.32 mmol) gave 97 mg (yield: HPLC/MS (15 minutes) retention time 8.87 minutes. LRMS: miz 595 (M+) Example 7

3-((5-(3,5-二氣吼啶-4-基胺基)-1-羥基-8,8-二甲基 -6,7,8,9-四氫-3H-吡唑並[3,4-c]異喹啉-3·基）甲基)苯甲酸將3-((5-(3,5-二氯吡啶-4-基胺基)-1-羥基-8,8-二甲基 32 201031663 -6,7,8,9-四氳-3Η-α比唆並[3,4-c]異啥琳-3-基）甲基)苯甲酸曱 ^ 酯（80毫克，0.15毫莫耳）溶解於THF (2毫升）中且添加氫氧化鋰（20毫克，0.48毫莫耳）之水（〇.5毫升）溶液。於室溫下攪拌反應混合物隔夜。於減壓下蒸發溶劑且將殘餘物懸浮於水中。用2 N HC1酸化直至pH = 3後，固體沈澱，過濾且用水以及***洗滌。獲得51毫克最終產物。產率=65%。 ❹ 4 NMR (200 MHz，DMSO_i/6) δ ppm 1.00 (s，6 H) 1.65 (s, 2 H) 2.65 (s, 2 H) 2.79 (s, 2 H) 4.94 (s, 2 H) 7.36 (d, J=7.03 Hz, 2 H) 7.69 (s, 1 H) 7.79 (d, J=7.81 Hz, 1 H) 8.30 (s, 1 H) 8.65 (s, 2 H) 實例83-((5-(3,5-dioxacridin-4-ylamino)-1-hydroxy-8,8-dimethyl-6,7,8,9-tetrahydro-3H-pyrazole And [3,4-c]isoquinolin-3-yl)methyl)benzoic acid 3-((5-(3,5-dichloropyridin-4-ylamino)-1-hydroxy-8, 8-Dimethyl 32 201031663 -6,7,8,9-tetraindole-3Η-α 唆[[3,4-c]isoindol-3-yl)methyl)benzoate oxime ester (80 </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was suspended in water. After acidification with 2 N HCl until pH = 3, the solid precipitated, filtered and washed with water and diethyl ether. Obtained 51 mg of the final product. Yield = 65%. ❹ 4 NMR (200 MHz, DMSO_i/6) δ ppm 1.00 (s, 6 H) 1.65 (s, 2 H) 2.65 (s, 2 H) 2.79 (s, 2 H) 4.94 (s, 2 H) 7.36 ( d, J=7.03 Hz, 2 H) 7.69 (s, 1 H) 7.79 (d, J=7.81 Hz, 1 H) 8.30 (s, 1 H) 8.65 (s, 2 H) Example 8

❹ 5-(3,5-二氯吡啶-4-基胺基)-8,8_二曱基-3-(吡啶-3-基曱基)-6,7,8,9-四氮-3Η-"比唑並[3,4-c]異喹啉-1-醇根據實例4中所述之方法，使實例1之標題化合物（50 毫克，0.13毫莫耳）與3-氯甲基吼啶（21毫克，0.16毫莫耳）反應，得到6毫克（10%)標題化合物。 HPLC/MS ( 15分鐘）滯留時間7.35分鐘。 LRMS: m/z 469 (M+) 實例9 33 201031663❹ 5-(3,5-Dichloropyridin-4-ylamino)-8,8-dimercapto-3-(pyridin-3-ylindenyl)-6,7,8,9-tetrazole- 3Η-"Bizozolo[3,4-c]isoquinolin-1-ol The title compound of Example 1 (50 mg, 0.13 mmol) and 3-chloromethyl was obtained according to the procedure described in Example 4. Reaction with acridine (21 mg, 0.16 mmol) gave 6 mg (10%) of the title compound. HPLC/MS (15 minutes) retention time 7.35 minutes. LRMS: m/z 469 (M+) Example 9 33 201031663

NN

Cl Β「，γΝΗ2Cl Β", γΝΗ2

cVH2 2-(5-(3,5-二氣I»比啶_4_基胺基)小羥基_8,8_二甲基 -6,7,8,9-四氫·3Η-吡唑並[3,4-c】異喹啉_3_基）乙醯胺根據實例4中所述之方法，使實例1之標題化合物（5〇毫克’ 0.13毫莫耳）與3_溴乙醯胺（2〇毫克，0.15毫莫耳）反應，得到8毫克（14%)標題化合物。 HPLC/MS ( 15分鐘）滯留時間7.28分鐘。 LRMS: miz 435 (M+) 實例10cVH2 2-(5-(3,5-digas I»pyridyl-4-ylamino)hydroxyl-8,8-dimethyl-6,7,8,9-tetrahydro-3Η-pyrazole And [3,4-c]isoquinoline-3-yl)acetamide The title compound of Example 1 (5 〇 mg '0.13 mmol) and 3 br. Reaction of the amine (2 mg, 0.15 mmol) gave 8 mg (14%) of the title compound. HPLC/MS (15 minutes) retention time 7.28 minutes. LRMS: miz 435 (M+) Example 10

3-((5-(3,5-二氣吡啶-4-基胺基)-1-羥基-8,8-二甲基 -6,7,8,9-四氫-3H-吡唑並[3,4-c]異喹啉-3-基）甲基）苯甲醯胺根據實例4中所述之方法，使實例1之標題化合物 (100毫克，0.26毫莫耳）與3-(演曱基)苯曱醯胺（73毫克， 0.32毫莫耳）反應，得到8毫克（14%)標題化合物。 4 NMR (200 MHz,氣仿-岣5?卩1!11.07(3,6 11)1.21-1.31 (m, 2 Η) 1.63 - 1.84 (m, 2 Η) 2.62 - 2.77 (m, 2 Η) 3.00 (s, 2 Η) 4.97 (s, 2 Η) 6.52 (s, 1 Η) 7.35 - 7.47 (m, 2 Η) 7.69 (s, 1 Η) 7.93 (s, 1 Η) 8.56 (s, 2 Η) 8.97 (s, 1 Η) 2010316633-((5-(3,5-dioxapyridin-4-ylamino)-1-hydroxy-8,8-dimethyl-6,7,8,9-tetrahydro-3H-pyrazole [3,4-c]isoquinolin-3-yl)methyl)benzamide The title compound of Example 1 (100 mg, 0.26 mmol) and 3- Reaction of phenylhydrazine (73 mg, 0.32 mmol) gave 8 mg (14%) of the title compound. 4 NMR (200 MHz, gas-like 岣5?卩1!11.07(3,6 11)1.21-1.31 (m, 2 Η) 1.63 - 1.84 (m, 2 Η) 2.62 - 2.77 (m, 2 Η) 3.00 (s, 2 Η) 4.97 (s, 2 Η) 6.52 (s, 1 Η) 7.35 - 7.47 (m, 2 Η) 7.69 (s, 1 Η) 7.93 (s, 1 Η) 8.56 (s, 2 Η) 8.97 (s, 1 Η) 201031663

HPLC/MS ( 15分鐘）滯留時間6·27分鐘。 LRMS: mfz5\\ (M+) 實例11HPLC/MS (15 minutes) retention time 6.27 minutes. LRMS: mfz5\\ (M+) Example 11

4_((5-(3,5-二氣0比咬-4-基胺基)-1-經基-8,8-二甲基 -6,7,8,9·四氳-3H-吡唑並[3,4-c]異喹啉_3·基）甲基）苯甲酸曱酯根據實例4中所述之方法，使實例1之標題化合物 (100毫克，0.26毫莫耳）與(溴甲基)苯曱酸甲酯（73毫克， 0.32毫莫耳）反應，得到41毫克（29%)標題化合物。4-((5-(3,5-diox0-biti-4-ylamino)-1-yl)-8,8-dimethyl-6,7,8,9·tetraindole-3H-pyridyl The title compound (100 mg, 0.26 mmol) of the compound of Example 1 was obtained according to the method described in Example 4, using oxazolo[3,4-c]isoquinolin-3-yl)methyl)benzoate. Reaction with methyl bromomethyl)benzoate (73 mg, 0.32 mmol) gave 41 mg (29%)

lU NMR (200 MHz, DMSO-i/6) δ ppm LOO (s, 6 H) 1.65 (m, 2 H) 2.65 (m, 2 H) 2.79 (s, 2 H) 3.85 (s, 3H) 4.94 (s, 2 H) 7.20 (d, J=7.03 Hz, 2 H) 7.85 (d, J=7.81 Hz, 1 H) 8.30 (bs, 1 H) 8.65 (s, 2 H) 10.6 (bs, 1H). HPLC/MS ( 9分鐘）滯留時間6.88分鐘。 LRMS: m/z 526 (M+) 實例12lU NMR (200 MHz, DMSO-i/6) δ ppm LOO (s, 6 H) 1.65 (m, 2 H) 2.65 (m, 2 H) 2.79 (s, 2 H) 3.85 (s, 3H) 4.94 ( s, 2 H) 7.20 (d, J=7.03 Hz, 2 H) 7.85 (d, J=7.81 Hz, 1 H) 8.30 (bs, 1 H) 8.65 (s, 2 H) 10.6 (bs, 1H). HPLC/MS (9 minutes) retention time 6.88 minutes. LRMS: m/z 526 (M+) Example 12

35 201031663 4-((5-(3,5-二氣吡啶-4-基胺基)-1-羥基-8,8-二甲基 -6,7,8,9-四氫-3H-吡唑並[3,4-c]異喹啉-3-基）甲基)苯甲酸根據實例7中所述之方法，使實例11之標題化合物 (40毫克，0.08毫莫耳）與氳氧化鋰（9.6毫克，0.23毫莫耳）反應，得到38毫克（98%)標題化合物。35 201031663 4-((5-(3,5-Di-pyridin-4-ylamino)-1-hydroxy-8,8-dimethyl-6,7,8,9-tetrahydro-3H-pyridyl The oxazolo[3,4-c]isoquinolin-3-yl)methyl)benzoic acid gave the title compound of Example 11 (40 mg, 0.08 m. (9.6 mg, 0.23 mmol) gave 38 mg (98%).

!H NMR (400 MHz, DMSO-J6) δ ppm 1.00 (s, 6 Η) 1.64 (t, J=626 Hz, 2 H) 2.64 (t, J=6.26 Hz, 2 H) 2.79 (s, 2 H) 4.94 (s, 2 H) 7.15 (d, 7=8.22 Hz, 2 H) 7.81 (d, J=8.22 Hz, 2 H) 8.33 (s, 1 H) 8.66 (s, 2 H) HPLC/MS ( 15分鐘）滯留時間8.26分鐘。 LRMS: m/z 512 (M+) 實例13!H NMR (400 MHz, DMSO-J6) δ ppm 1.00 (s, 6 Η) 1.64 (t, J=626 Hz, 2 H) 2.64 (t, J=6.26 Hz, 2 H) 2.79 (s, 2 H ) 4.94 (s, 2 H) 7.15 (d, 7 = 8.22 Hz, 2 H) 7.81 (d, J = 8.22 Hz, 2 H) 8.33 (s, 1 H) 8.66 (s, 2 H) HPLC/MS ( 15 minutes) The residence time is 8.26 minutes. LRMS: m/z 512 (M+) Example 13

3-((5-(3,5-二氣啦啶-4-基胺基)-1-羥基-8,8_二甲基 -6,7,8,9-四氫-3H-吡唑並[3,4-c】異喹啉-3-基）曱基)苯甲腈3-((5-(3,5-dioxalp-4-ylamino)-1-hydroxy-8,8-dimethyl-6,7,8,9-tetrahydro-3H-pyrazole And [3,4-c]isoquinolin-3-yl)indolylbenzonitrile

根據實例4中所述之方法，使實例1之標題化合物（50 毫克，0.13毫莫耳）與3-(演曱基)苯曱腈（31毫克，0.16 毫莫耳）反應，得到17毫克（26%)標題化合物。屯 NMR (200 MHz，氯仿δ ppm 0.92 - 1.19 (m, 6 H) 1.60 - 1.85 (m, 2 Η) 2.58 - 2.79 (m, 2 Η) 2.90 - 3.03 (m, 2 Η) 5.08 (s, 2 Η) 6.47 (s, 2 Η) 7.42 - 7.65 (m, 4 Η) 8.56 (s, 2 Η) 36 201031663The title compound of Example 1 (50 mg, 0.13 mmol) was reacted with 3-(decyl)benzonitrile (31 mg, 0.16 mmol) according to the procedure described in Example 4 to afford 26%) title compound.屯NMR (200 MHz, chloroform δ ppm 0.92 - 1.19 (m, 6 H) 1.60 - 1.85 (m, 2 Η) 2.58 - 2.79 (m, 2 Η) 2.90 - 3.03 (m, 2 Η) 5.08 (s, 2 Η) 6.47 (s, 2 Η) 7.42 - 7.65 (m, 4 Η) 8.56 (s, 2 Η) 36 201031663

實例14Example 14

4-((5-(3,5-二氣π比咬-4-基胺基)-1-經基-8,8·二甲基 -6,7,8,9_四氫-3Η-吡唑並[3,4-c]異喹啉-3-基）曱基）苯曱醯胺根據實例4中所述之方法，使實例1之標題化合物（50 毫克，0.13毫莫耳）與4-(溴甲基)苯甲醯胺（34毫克，0.16 毫莫耳，參見製備9)反應，得到10毫克（14%)標題化合物。4-((5-(3,5-digas π 咬-4-ylamino)-1-yl-yl-8,8-dimethyl-6,7,8,9-tetrahydro-3Η- Pyrazolo[3,4-c]isoquinolin-3-yl)indolyl benzoguanamine The title compound of Example 1 (50 mg, 0.13 mmol) was obtained according to the procedure described in Example 4. 4-(Bromomethyl)benzamide (34 mg, 0.16 mmol, see Preparation 9) gave 10 mg (14%)

4 NMR (200 MHz，氯仿-均3卩卩1!11.05(3,6 11)1.21-1.31 (m, 2 Η) 1.63 - 1.84 (m, 2 Η) 2.62 - 2.77 (m, 2 Η) 3.00 (s, 2 Η) 4.95 (s, 2 Η) 6.52 (s, 1 Η) 7.15 (d, J=8.22 Hz, 2 H) 7.81 (d, /=8.22 Hz, 2 H) 8.56 (s, 2 H) 8.97 (s, 1 H) HPLC/MS (9分鐘）滯留時間6.19分鐘。 LRMS: m/z 511 (M+) 實例154 NMR (200 MHz, chloroform-average 3卩卩1!11.05(3,6 11)1.21-1.31 (m, 2 Η) 1.63 - 1.84 (m, 2 Η) 2.62 - 2.77 (m, 2 Η) 3.00 ( s, 2 Η) 4.95 (s, 2 Η) 6.52 (s, 1 Η) 7.15 (d, J=8.22 Hz, 2 H) 7.81 (d, /=8.22 Hz, 2 H) 8.56 (s, 2 H) 8.97 (s, 1 H) HPLC/MS (9 min) retention time 6.19 min. LRMS: m/z 511 (M+) Example 15

5-(3,5-二氣》比啶-4-基胺基)-8,8_二甲基-3-(3-(N-嗎啉基)丙基)-6,7,8,9-四氫_3Η·吼唑並[3,4-c]異喹啉-1-醇 37 201031663 根據實例4中所述之方法，使實例1之標題化合物（88 毫克，0.23毫莫耳）與甲磺酸3-(N-嗎啉基)丙醋（62毫克， 0.28毫莫耳，參見製備10)反應，得到22毫克（26%) 標題化合物。 4 NMR (200 MHz,氯仿-β〇 δ ppm 1.08 (s，6 H) 1.25 (m, 2 Η) 1.75 (t, 2 Η) 2.00 (m, 2 Η) 2.50 - 2.70 (m, 8 Η) 2.95 (s, 2 Η) 3.8 - 3.9 (m, 4 Η) 6.47 (s, 1 Η) 8.50 (s, 2 Η)5-(3,5-diqi)pyridin-4-ylamino)-8,8-dimethyl-3-(3-(N-morpholinyl)propyl)-6,7,8, 9-Tetrahydro- 3 Η·oxazolo[3,4-c]isoquinolin-1-ol 37 201031663 The title compound of Example 1 (88 mg, 0.23 mmol) was obtained according to the procedure described in Example 4. Reaction with 3-(N-morpholinyl)propaneacetic acid methanesulfonate (62 mg, 0.28 mmol, mp. 4 NMR (200 MHz, chloroform-β〇δ ppm 1.08 (s, 6 H) 1.25 (m, 2 Η) 1.75 (t, 2 Η) 2.00 (m, 2 Η) 2.50 - 2.70 (m, 8 Η) 2.95 (s, 2 Η) 3.8 - 3.9 (m, 4 Η) 6.47 (s, 1 Η) 8.50 (s, 2 Η)

HPLC/MS ( 30分鐘）滯留時間9.36分鐘。 LRMS: m!z 505 (M+) 實例16HPLC/MS (30 minutes) retention time 9.36 minutes. LRMS: m!z 505 (M+) Example 16

3-(3-(5-(3,5-二氣嘥啶-4-基胺基)-1_羥基_8,8_二曱基 -6,7,8,9·四氫-3H-吡唑並[3,4-c]異喹啉-3-基）丙基)苯甲腈3-(3-(5-(3,5-dioxacridin-4-ylamino)-1_hydroxy-8,8-dimercapto-6,7,8,9·tetrahydro-3H- Pyrazolo[3,4-c]isoquinolin-3-yl)propyl)benzonitrile

根據實例4中所述之方法，使實例1之標題化合物（70 毫克，0.19毫莫耳）與3-(3-溴丙基)苯曱腈（50毫克，0.22 毫莫耳，參見製備11)反應，得到42毫克（44%)標題化合物。 4 NMR (200 MHz，氯仿δ ppm 1_08 (s, 6 H) 1.75 (s, 2 Η) 2.11 (s, 2 Η) 2.42 - 2.77 (m, 4 Η) 2.95 (s, 2 Η) 3.79 -4.12 (m, 2 Η) 6.47 (s, 1 Η) 7.18 - 7.54 (m, 4 Η) 8.50 (s, 2 Η) 實例17 38 201031663The title compound of Example 1 (70 mg, 0.19 mmol) and 3-(3-bromopropyl)benzonitrile (50 mg, 0.22 mmoles, see Preparation 11) was obtained according to the procedure described in Example 4. Reaction gave 42 mg (44%) of the title compound. 4 NMR (200 MHz, chloroform δ ppm 1_08 (s, 6 H) 1.75 (s, 2 Η) 2.11 (s, 2 Η) 2.42 - 2.77 (m, 4 Η) 2.95 (s, 2 Η) 3.79 -4.12 ( m, 2 Η) 6.47 (s, 1 Η) 7.18 - 7.54 (m, 4 Η) 8.50 (s, 2 Η) Example 17 38 201031663

3-(3-(5-(3,5_二氣吼咬_4_基胺基)q遍基_8,8_ -6,7,8,9-四氫_3Η·他唾並[3,4_c】異噎琳_3基）丙基)苯甲醜 Ο3-(3-(5-(3,5_二气吼 bit_4_ylamino)q-transyl _8,8_ -6,7,8,9-tetrahydro _3Η·he saliva[3 , 4_c] 噎噎 _3 base) propyl) benzoquinone ugly

根據實例4中所述之方法，使實例i之標題化合物⑺ 毫克’ 0.19毫莫耳）與3_(3·漠丙基)苯甲醯胺（54 0.22毫莫耳，參見製備12)反應，得到％毫克（5 標題化合物。 H NMR (200 MHz，氯仿_心？1)1111〇6(5,611)156_ 1.80 (m, 2 Η) 1.93 - 2.19 (m, 2 Η) 2.38 - 2.76 (m, 4 Η) 2.98 (s, 3 Η) 3.88 (t, J=6.64 Hz, 2 H) 6.59 (s, 1 H) 7.15 - 7.43 (m, 4 H) 7.55 - 7.71 (m, 2 H) 8.47 (s，2 H) 藥理活性 PDE4檢定程序使用 PH] cAMP 閃爍親近檢定（Scintillation Proximity Assay，SPA) (GE Healthcare)量測鱗酸二酯酶活性。將待測試之化合物以1 mM之原料濃度溶解於二曱亞碾 (DMSO)中且用5〇%DMSO製備連續稀釋液以測定IC50。於室溫下在96孔板（Coming，Ref.3604)中，在抑制劑存在或不存在下，在〇.1毫升含有以下（最終濃度）之反應缓衝液中進行反應：50mMTris_HCl (pH7.5)、8.3 mMMgCl2、1.7mM乙二醇雙（2-胺基乙基醚）四乙酸 39 201031663 (EGTA)'^ nM PH] cAMP (每孔約 150000 次衰變/分 (dpm))。藉由添加重組pDE4酶之酵母萃取物來起始反應。The title compound (7) mg [0.19 mmol] of Example i was reacted with 3-(3················· % mg (5 title compound. H NMR (200 MHz, chloroform_heart? 1) 1111〇6(5,611)156_ 1.80 (m, 2 Η) 1.93 - 2.19 (m, 2 Η) 2.38 - 2.76 (m, 4 Η ) 2.98 (s, 3 Η) 3.88 (t, J=6.64 Hz, 2 H) 6.59 (s, 1 H) 7.15 - 7.43 (m, 4 H) 7.55 - 7.71 (m, 2 H) 8.47 (s, 2 H) Pharmacologically active PDE4 assay procedure Quantitative bisphosphonate activity was measured using the PH] cAMP scintillation Proximity Assay (SPA) (GE Healthcare). The compound to be tested was dissolved in diterpenoid at a concentration of 1 mM. Serial dilutions were prepared in milled (DMSO) and prepared in 5% DMSO to determine the IC50. At room temperature in 96-well plates (Coming, Ref. 3604), in the presence or absence of inhibitors, in 1.1 ml The reaction was carried out in the reaction buffer containing the following (final concentration): 50 mM Tris_HCl (pH 7.5), 8.3 mMMgCl2, 1.7 mM ethylene glycol bis(2-aminoethyl ether) tetraacetic acid 39 201031663 (EGTA) '^ nM PH ] cAMP ( Approximately 150,000 decays per minute (dpm). The reaction was initiated by the addition of a yeast extract of recombinant pDE4 enzyme.

於室溫下震盪各板1小時且藉由在硫酸鋅存在下添加 50微升（〇.5毫克/孔）SPA矽酸釔珠粒（RPNQ0150 ; GE Healthcare)來終止培育。避光儲存各板隔夜且在TRIUJX 微量滴定板讀取器（PerkinElmer)上讀數。結果展示於表1中。實例 IC50 (nM) 1 3.90 2 62.00 3 16.80 4 11.00 5 17.10 6 2.00 7 3.10 8 7.40 9 18.8 10 2.30 12 2.40 13 2.35 14 5.17 15 6.14 _ 16 15.50 17 2.10 .. 自表1可見，式（I)化合物是鱗酸一醋酶4 (PDE 4 ) 之極有效抑制劑。所述化合物亦能夠阻斷一些促發炎性細胞激素（例如TNFa)之產生。因此，其可用於治療過敏、發炎性以及免疫疾病，以 201031663 “ 及阻斷促發炎性細胞激素或選擇性抑制PDE 4可能有利之疾病或病狀。此等疾病狀況包含哮喘、慢性阻塞性肺病、過敏性鼻炎、類風濕性關節炎、骨關節炎（〇ste〇arthritis)、骨質疏鬆症（osteoporosis)、骨形成病症（bone-formati〇n dlsorder)、絲球體腎炎（glomerulonephritis)、多發性硬化症、強直性脊椎炎（ankylosing spondylitis)、格雷夫氏眼病（Graves ophtalmopathy )、重症肌無力（myasthenia ❹ gravis)、尿崩症（diabetes insipidus)、移植排斥反應、腸胃障礙（gastrointestinal disorder )(諸如大腸急躁病 (irritable bowel disease )、潰瘍性結腸炎（ulcerative c〇litis ) 或克羅恩氏病（Crohn disease ))、敗血性休克（septic shock)成人呼吸窘迫症候群distress respiratory syndrome)以及皮膚病（諸如異位性皮膚炎、接觸性皮膚炎（contact dermatitis )、急性皮肌炎（acute dermatomy〇sitis ) 以及牛皮癬）。其亦可用作腦血管功能之改良劑，以及用於〇治療其他中枢神經系統（CNS)相關疾病（諸如癡呆、阿兹海默氏病（Alzheimer’s disease)、抑鬱症），以及用作益智劑（nootropic agent)。類似其他PDE4抑制劑（參見以上參考文獻），本發明之化合物亦可用於在預防性以及/或治癒性處理後阻斷由各種病原劑（諸如消炎藥（類固醇或非類固醇消炎劑）、壓力、氨、酒精以及濃酸）誘發之糜爛以及潰瘍作用。其可單獨用於或與抗酸劑以及/或抗分泌藥組合用於預防性以及/或治癒性處理腸胃病理，如藥物誘發性潰瘍 201031663 (dmg-mducedulceO、消化性潰瘍（pepticulcer)、幽門螺: 說才干相關/貝瘍（H. Pyi〇ri_reiated uicer )、食道炎〜 (esophagitis )以及胃食道逆流疾病（叩hageal reflux disease) ° 其亦可用於治療由如缺氧或產生過量自由基之條件對細胞或組織造成損傷的病理狀況。所述有益作用之實例為在冠狀動脈阻塞後保護心臟組織，或當將本發明之化合物添加至欲用於儲存移植器官或流體（諸如錢或***） ❹ =保存液（preserving solution)中時，延長細胞以及組織筹命。其亦有利於組織修復以及創傷癒合。本發明之化合物亦可與已知有效治療此等疾病之例如（a) β2腎上腺素激導性促效劑、⑻抗膽驗劑、（c) 抗過敏劑、（d)消炎劑、（e)免疫抑制劑以及（f)抗感染劑之其他祕組合個_時、分開或依相於治療人體或動物體。因此，本發明之另一實施例是式⑴化合物用於製造供治療或預防已知易藉由抑制PDE4來改善之病理學病 _ 狀、疾病以及病症之藥劑的用途，以及—種治療罹患易藉由抑制PDE4來改善之病理病狀或疾病之個體的方法，所述方法包括向所述個體投與有效量之式（1)化合物。小本發明亦提供醫藥組合物，其包括作為活性成份之至夕—種式（I)之四氫《比唑並[3,4-c]異喹琳胺衍生物或其 2藥學上可接受之鹽’以及醫藥學上可接受之賦形劑（諸載劑或稀釋劑）。所述活性成份可包括〇·⑻1重量％至99 42 201031663 較佳〇.01重置％至90重量°/〇所述組合物，此視調二：性質以及在施用之前是否作進-步稀釋而定。組合合於經口、吸入、局部、經鼻、直腸、經皮或可注射投與之形式構成。 Μ所述化合物之舰合形成本發明之、/的4樂予上可接受之賦_The plates were shaken for 1 hour at room temperature and incubation was stopped by the addition of 50 microliters (0.5 mg/well) of SPA bismuth citrate beads (RPNQ0150; GE Healthcare) in the presence of zinc sulfate. Plates were stored overnight in the dark and read on a TRIUJX microtiter plate reader (PerkinElmer). The results are shown in Table 1. Example IC50 (nM) 1 3.90 2 62.00 3 16.80 4 11.00 5 17.10 6 2.00 7 3.10 8 7.40 9 18.8 10 2.30 12 2.40 13 2.35 14 5.17 15 6.14 _ 16 15.50 17 2.10 .. Compounds of formula (I) can be seen from Table 1. It is a very potent inhibitor of chlorate-acetase 4 (PDE 4 ). The compounds are also capable of blocking the production of some pro-inflammatory cytokines such as TNFa. Therefore, it can be used to treat allergies, inflammatory and immune diseases to 201031663 "and to block diseases or conditions that promote inflammatory cytokines or selectively inhibit PDE 4. These diseases include asthma, chronic obstructive pulmonary disease , allergic rhinitis, rheumatoid arthritis, osteoarthritis (ostste〇arthritis), osteoporosis (osteoporosis), bone formation disorder (bone-formati〇n dlsorder), glomerulonephritis (glomerulonephritis), multiple sclerosis Disease, ankylosing spondylitis, Graves ophtalmopathy, myasthenia gra gravis, diabetes insipidus, transplant rejection, gastrointestinal disorder (such as the large intestine) Irritable bowel disease, ulcerative colitis (Crohn disease), septic shock, distress respiratory syndrome, and dermatosis (such as urinary septic shock) Atopic dermatitis, contact dermatitis ), acute dermatomy〇sitis and psoriasis. It can also be used as a modifier for cerebrovascular function, as well as for the treatment of other central nervous system (CNS)-related diseases such as dementia and Alzheimer's disease. Alzheimer's disease, depression, and as a nootropic agent. Like other PDE4 inhibitors (see references above), the compounds of the invention may also be used in prophylactic and/or curative treatment Post-blocking erosion and ulceration induced by various pathogens such as anti-inflammatory drugs (steroids or non-steroidal anti-inflammatory agents), stress, ammonia, alcohol, and concentrated acids. It can be used alone or with antacids and/or anti-drugs. Combination of secretory drugs for prophylactic and/or curative treatment of gastrointestinal pathology, such as drug-induced ulcers 201031663 (dmg-mducedulceO, peptic ulcer, pylori snail: sedative related / snail (H. Pyi〇ri_reiated uicer ), esophagitis ~ (esophagitis) and gastroesophageal reflux disease (叩hageal reflux disease) ° It can also be used for treatment such as hypoxia or The conditions that cause free radical damage pathological condition of cells or tissues. An example of such a beneficial effect is to protect heart tissue after coronary artery occlusion, or when a compound of the invention is added to a storage organ or fluid (such as money or sperm) ❹ = preserving solution, Extend cells and organize your life. It also facilitates tissue repair and wound healing. The compounds of the present invention may also be, for example, (a) a β-adrenergic agonist, (8) an anti-cholestasis agent, (c) an anti-allergic agent, (d) an anti-inflammatory agent, (e) known to be effective in the treatment of such diseases. The immunosuppressive agent and (f) other secret combinations of anti-infective agents are treated separately or separately to treat the human or animal body. Accordingly, another embodiment of the present invention is the use of a compound of formula (1) for the manufacture of a medicament for the treatment or prevention of pathological conditions, diseases and conditions known to be ameliorated by inhibition of PDE4, and A method of ameliorating a subject of a pathological condition or disease by inhibiting PDE4, the method comprising administering to the individual an effective amount of a compound of formula (1). The present invention also provides a pharmaceutical composition comprising as an active ingredient an tetrahydrogen "biszolo[3,4-c]isoquinolamine derivative of formula (I) or a pharmaceutically acceptable compound thereof a salt' and a pharmaceutically acceptable excipient (carrier or diluent). The active ingredient may comprise 〇·(8)1% by weight to 99 42 201031663 preferably 〇.01 reset % to 90 weight 〇/〇 of the composition, this visual 2: nature and whether or not to be diluted before application And set. The combination is in the form of oral, inhalation, topical, nasal, rectal, transdermal or injectable administration.舰The compound of the compound forms the 4th of the present invention.

用之賦形劑視所欲投與組合物之方法而定。貫丁斤用於經口投與之組合物可採用键劑、延遲型鍵劑、舌囊、吸人型氣溶膠、吸人型溶液、乾粉吸入劑 r文體諸如混合物、醜劑、糖漿或懸浮液）之形式， =形式均含有本伽德合物；所述㈣可藉由此項技術中熟知之方法來製備。、可用於製備組合物之稀釋劑包含與活性成份相容之 =體以及固體稀釋劑，以及必要時選用之著色劑或調味蜊。錠劑或膠囊宜含有介於001_30⑽毫克之間、更佳 0.5-1000毫克活性成份或等量之其醫藥學上可接受之鹽r 適合於經口使用之液體組合物可呈溶液或懸浮液之形式。所述频可為活性化合物之可雜贱其他衍生物之水溶液，例如與蔗糖形成糖漿。所述懸浮液可包括本發明之不溶性活性化合物或其醫鮮上可接受之鹽以及水以及懸浮劑或調味劑。用於非經腸注射之組合物可由可溶性鹽製備，其可能為或不為凍乾形式且可溶解於無熱原水性介質或其他= 非經腸注射流體中。 ' 曰 43 201031663 用於局部投與之組合物可採用軟膏、乳式，所有形式均含有本發明之化合物；劑；^ ^ 項技術中熟知之方法來製備。 μ j藉由此有效劑量通常為每日在__3〇〇〇亳克、更佳〇 5_1000 毫克範_之雜絲_4之其醫藥每曰劑量可以每日一或多次治瘆、軔# 了接又之孤式投與。彡人⑺療^^^次治療之形 ❹ 醫藥調配物可適宜地以單位劑型提學技術中熟知之任何方法來㈣。適合於經π投與之本發日狀舰物可以供丄位，諸如膠囊、扇囊劑(滅。或錠劑各3預疋里之活性成份；粉末或顆粒水液或懸浮液；或水包油液體乳液或油= 液體=液。活性成份亦可以大丸劑㈤Μ)、紙劑（心或糊劑形式提供。脑物-般將基本上由化合物或鹽於具有調味劑f =之液體載劑（例如乙醇、花生油、橄欖油、甘油或水）中之懸浮液或溶液組成。 )物呈^劑之形式時’可使用通常用於製備固體調配之壬何醫藥載劑。所述載劑之實例包含硬脂酸鎮、滑！她明膠、***膠（㈣ia)、硬脂酸、澱粉、乳糖以及庶糖。 Μ制藉::見情況與—或多種輔助成份-起壓縮或、 °製健劑可藉由在適合之機器中壓縮視情況 201031663 劑、潤滑劑、惰性稀釋劑、潤滑劑、表自活性劑或之呈自由流動形式(諸如粉末或顆粒)的活性釋劑可藉由錢合之機11巾㈣經惰性液體稀釋綱末狀化合物的混合物來製 :可包覆包衣或經刻痕且可進行調配以提供活性中之緩慢或控制釋放。攻伤在，、 ❹ ❿ 轉囊之形式時，任㈣職封均膠，吏用上述載劑。當組合物呈軟明柄，可考慮通常祕製備分舰·浮液之 3 = ϊ劑’例如水性樹膠(aqu_ gum)、纖維素、矽酸鹽或油類，且將其併入軟明膠膠囊中。例如至^之乾粉組合物可例如以心越，® 同（ldge)或例如層壓銘落之二1二bllSter)形式提供，以用於吸入器或吹入器中。 =物：般含有用於吸入本發明之化合物以及適合之粉末 :n、劑物質）（諸如乳糖或殿粉）之粉末混合物。較佳 4孔糖。每一膠囊或藥筒一般可含有介於0.001-50毫克 2，佳Ml_5毫克活性成份或等量之其醫藥學上可接丈:。或者’活性成份可在無賦形劑之情況下提供。劑量可適合於單位劑量或多劑量傳遞。在多社月況下調配物可預先計量或在使用時計量。 ^粉吸人器分為三組：（a)單次劑量、㈤多單位劑罝以及（c)多劑量裝置。 45 201031663 —對於第-類型之吸入器，單次劑量已由製造商稱量至：* 小谷器中’其主要是硬娜膠囊。職必須自獨立，容器取得且***吸入器之接收區中。接著，膠囊必ϊ用針或切刀（cutting blade)打開或穿孔以允許在吸入期間一部 :吸入空氣流穿過膠囊以帶走粉末或藉助於離心力經由此，開孔自膠囊排出粉末。吸人後，空膠囊必須再次自吸入器移除。***以及移除膠囊通常需要拆開吸入器，此操作對於一些患者可能是困難及麻煩的。 ❹ 與使用硬明膠膠囊來吸入粉末有關之其他缺點是（a) 防止自周圍空氣吸收水分之能力弱、（b)關於在膠囊預先暴露於極端相對濕度（此會引起斷裂或凹痕（indenture)) 後打開或穿孔之問題以及（c)可能吸入膠囊片段。此外，對於多種膠囊吸入器，已報導不完全排出（例如见咖如等人，1997)。如WO 92/03175中所述，一些膠囊吸入器具有倉匣 (magazine)，可自所述倉匣將個別膠囊轉移至接收室，在所述接收室中進行穿孔以及排空。其他膠囊吸入器具有的 Θ 旋轉倉匣帶有可與空氣導管成一直線以排出劑量之膠囊室 (例如WO91/02558以及GB 2242134)。其包括多單位劑量吸入器以及發泡藥吸入器之類型’其在盤狀物或帶狀物上供應有限量之單位劑量。與膠囊吸入器相比’發泡藥吸入器提供對藥劑之較好防潮保護。藉由在覆蓋物以及發泡箔上穿孔或藉由剝開覆蓋箔來獲得粉末。當使用發泡條狀物替代盤狀物時，可增 46 201031663 ; 加劑量數目，但患者更換空條狀物是不方便的。因此，具有所併有之劑量系統的所述裝置通常是拋棄式的，其包含用於傳送條狀物且打開發泡袋之技術。多劑量吸入器不含有預先量測數量之粉末調配物。其由相對大的容器以及必須由患者操作之劑量量測元件 (dose measuring principle)組成。所述容器帶有藉由體積排量（volumetric displacement)個別地與粉末主體分離之 © 多個劑量。存在多種劑量量測元件，包含可旋轉膜（例如 EP0069715)或盤狀物（例如 gb 2041763 ; EP 0424790 ; DE 4239402以及EP 0674533)、可旋轉圓柱體（例如EP 0166294 ; GB 2165159 以及 WO 92/09322)以及可旋轉錐台（例如WO 92/00771)，全部均具有必須填滿來自容器之粉末的空腔。其他多劑量裝置具有量測滑塊（例如US 5201308以及WO 97/00703)或量測活塞，其具有局部或圓周凹槽以將一定體積之粉末自容器移動至傳遞室或空氣The excipients used will depend on the method of administration of the composition. The composition for oral administration can be used as a key agent, a delayed type key agent, a tongue capsule, an inhalation type aerosol, an inhalation type solution, a dry powder inhalant r body such as a mixture, an ugly agent, a syrup or a suspension. In the form of liquid), the = form contains the native gamma compound; the (iv) can be prepared by methods well known in the art. The diluent which can be used in the preparation of the composition comprises a body and a solid diluent which are compatible with the active ingredient, and if necessary, a coloring agent or a flavoring agent. Tablets or capsules preferably contain between 001 and 30 (10) milligrams, more preferably 0.5 to 1000 milligrams of active ingredient or an equivalent amount of a pharmaceutically acceptable salt. r. Liquid compositions suitable for oral use may be in solution or suspension. form. The frequency may be an aqueous solution of the active compound which may be heterologous to other derivatives, for example to form a syrup with sucrose. The suspension may comprise the insoluble active compound of the present invention or a pharmaceutically acceptable salt thereof, as well as water and a suspending or flavouring agent. Compositions for parenteral injection may be prepared from soluble salts, which may or may not be in lyophilized form and which may be dissolved in a pyrogen-free aqueous medium or other = parenteral injection fluid. ' 曰 43 201031663 Compositions for topical administration may be prepared by ointments, emulsions, all forms containing the compounds of the invention; agents; methods well known in the art. The effective dose of μ j is usually __3 gram per day, more preferably _5_1000 milligrams of _ _ _ 4 of its medicine, each dose can be treated one or more times a day, 轫# After the solitary cast. Deaf (7) Treatment ^^^ The shape of the treatment ❹ The pharmaceutical formulation may suitably be in any of the methods well known in the art of unit dosage formulation (4). It is suitable for 丄投本日日日可以 , , , , , , , , , , , , , , , , , , , , , , π π π π π π π π π π π π π π π π π π π π Oil-in-water emulsion or oil = liquid = liquid. The active ingredient can also be provided in the form of a bolus (5) 、), paper (heart or paste). The brain will generally consist essentially of a compound or salt in a liquid with a flavoring agent f = A suspension or solution of the agent (for example, ethanol, peanut oil, olive oil, glycerin or water) can be used as a pharmaceutical carrier which is generally used for the preparation of solid formulations. Examples of such carriers include stearic acid towns, slippery! She is gelatin, gum arabic ((iv) ia), stearic acid, starch, lactose and sucrose.借制:: See the situation and - or a variety of auxiliary ingredients - from compression or °, the health agent can be compressed by a suitable machine 201031663 agents, lubricants, inert diluents, lubricants, self-active agents Or an active release agent in a free-flowing form (such as a powder or granules) may be prepared by mixing a mixture of the compound with an inert liquid by a machine 11 (4): coated or scored and Formulation is provided to provide slow or controlled release of activity. When the attack is in the form of , ❿ ❿ ❿ , 任任任任任任任任任任任任任任任任任任任任任任任When the composition is in the form of a soft handle, consider the usual secret preparation of the splitter/floating liquid 3 = tincture 'such as water-based gum (aqu_ gum), cellulose, citrate or oil, and incorporate it into soft gelatin capsules. in. For example, a dry powder composition of the type can be provided, for example, in the form of a heart, a ldge or a laminate, for example, in the form of a laminate, for use in an inhaler or insufflator. = substance: a powder mixture which is generally used for inhaling the compound of the present invention and a suitable powder: n, a substance (such as lactose or house powder). Preferably, 4 pores of sugar. Each capsule or cartridge may generally contain between 0.001 and 50 mg 2 , preferably Ml 5 mg active ingredient or equivalent in pharmaceutically acceptable form: Alternatively, the active ingredient can be provided without excipients. The dosage can be adapted for delivery in unit dose or multiple doses. The formulation may be pre-measured or metered at the time of use. There are three groups of powder inhalers: (a) single dose, (f) multiple unit doses, and (c) multiple dose devices. 45 201031663 - For the first type of inhaler, a single dose has been weighed by the manufacturer to: * in the small barn' which is mainly the Jona capsule. The job must be taken from the stand-alone container and inserted into the receiving area of the inhaler. Next, the capsule must be opened or perforated with a needle or cutting blade to allow for a portion of the inhalation air flow through the capsule to carry away the powder or by means of centrifugal force, through which the opening discharges the powder from the capsule. After inhaling, the empty capsule must be removed from the inhaler again. Inserting and removing the capsule usually requires disassembling the inhaler, which can be difficult and cumbersome for some patients.其他 Other disadvantages associated with the use of hard gelatin capsules to inhale powder are (a) the ability to prevent moisture absorption from the surrounding air, and (b) the pre-exposure to extreme relative humidity in the capsule (this can cause breaks or indentations) The problem of opening or perforating and (c) possibly inhaling the capsule fragments. In addition, incomplete inhalation has been reported for a variety of capsule inhalers (see, for example, et al., 1997). As described in WO 92/03175, some capsule inhalers have magazines from which individual capsules can be transferred to a receiving chamber where perforation and evacuation are performed. Other capsule inhalers have a 旋转 rotating cartridge with a capsule chamber that is lined up with the air conduit to expel the dose (e.g., WO 91/02558 and GB 2242134). It includes a multi-unit dose inhaler and a type of foaming inhaler that supplies a limited amount of unit dose on a disc or ribbon. The foaming drug inhaler provides better moisture protection for the medicament than the capsule inhaler. The powder is obtained by perforating the cover and the foamed foil or by peeling off the cover foil. When a foamed strip is used instead of a disc, it can be increased by 46 201031663; the number of doses is added, but it is inconvenient for the patient to replace the empty strip. Accordingly, the device having a dosage system of the same type is generally disposable, and includes a technique for conveying the strip and opening the foam bag. Multi-dose inhalers do not contain a pre-measured amount of powder formulation. It consists of a relatively large container and a dose measuring principle that must be operated by the patient. The container has a plurality of doses that are individually separated from the powder body by volumetric displacement. There are a variety of dose measuring elements, including a rotatable membrane (eg EP0069715) or a disc (eg gb 2041763; EP 0424790; DE 4239402 and EP 0674533), a rotatable cylinder (eg EP 0166294; GB 2165159 and WO 92/09322) And a rotatable frustum (for example WO 92/00771), all having a cavity that must be filled with powder from the container. Other multi-dose devices have measuring sliders (e.g., US 5201308 and WO 97/00703) or measuring pistons having partial or circumferential grooves to move a volume of powder from the container to the transfer chamber or air.

p 導官中（例如 EP 0505321、WO 92/04068 以及 WO 92/04928 );或量測滑塊，諸如Genuia_ (以前稱為 Novolizer SD2FL ) ’其在以下專利申請案中有描述：第 W097/000703 號、第 W003/000325 號以及第 W003/061742 號。可再現劑量量測是多劑量吸入器裝置之主要關注事項之一。粉末調配物必須展現良好且穩定的流動性質，因為劑量量測杯或空腔之填充主要受地心引力之影響。 47 201031663 '對於再裝翻單:域量減私器量測精確度以及再現性可由製造商確保。— _ ^ —万面，冬劍有較高數目之劑量，然而-般可減少裝填劑量測=多吸入空氣流通常徑直穿過劑量 I測工腔且因為多.吸人器之大塊系統不能由此吸入空氣流_，所以容=的^里里測塊且在排出期間獲得極少g結。斤4易自空腔帶走粉末因此，獨立崩解構件是必需的。然而總是吸入器設計之一部分。由於多劑:八量’故必須使空氣導管之内壁以及 ΐ力中=1:'須可，清潔此等部件，而= 直甲之幻餘劑$。—些多劑量吸人器器’其可在已服用規定數目劑量後進 =卿。對於具有拋棄式藥物容器之劑里吸入|^對防止#物㈣之要〇除了經由乾粉吸人器施用，本發明之 =投舆’其經由氣趙推進劑或藉助作’藉此可在高麼下嗜㈣扭w “、所明盗來細薄霧。此等喷霧器之優點在===: 參考其内容。次赐咖細7號中，本文用於藉由吸人局部傳遞至肺之喷餘合物可例如調 48 201031663 勹=^^生,合液或懸浮液或藉助於適合之液化推進劑自加壓如定劑量吸人11)傳遞之氣溶躁。適合於吸入之 ^/且合物可為懸浮液或溶液且—般含有活性成份以及人I»之隹進劑’諸如氣碳化物或含氳之氯氟碳化物或其混 I^ ，其為氫氟烷，例如二氯二氟甲烷、三氯氟甲烷、 ^四氟乙燒’尤其為mi四氟乙烧、mm、七 ❹ ❹ 作推二，或其此合物。二氧化碳或其他適合之氣體亦可用氣，^合物可無賦_或可姆齡有此項技術配物卿劑，諸如界面活性劑（如油酸或用閥二二劑(如乙醇)。加壓調配物一般將保存在罐：二穴間)封閉且與具備吸口之致動器配合的 ^於藉由狀投與之_適具有受餘#。用於吸入米。當吸人祕酬，尺^ ί。為達成此等粒徑，可藉由習知方= 如之二：緣:或過筛來分離出。所述粒子較佳將為結晶:Γ 難以達良流動性以及極端聚結趨勢而子在吸入器中時應較大，但在排μ 粒因此，-般使用諸如乳糖或葡萄糖月中。賦形劑之粒徑通常—大得乳 49 201031663 糖時’其通常將以經研磨之乳糖（較佳為結晶α單水合乳糖）形式提供。 σ 加壓氣溶膠組合物一般將填充至裝備有閥門（尤其為計量閥）之罐中。罐可視情況塗有塑膠材料，例^如 W096/32150中所述之氟碳聚合物。將罐與適合於頰内傳遞之致動器配合。用於經鼻傳遞之典型組合物包含上述用於吸入之组合物且進一步包含呈存於惰性媒劑（諸如水）中之溶液或懸浮液形式的非加壓組合物，其視情況與可藉由鼻泵投與之習知賦形劑（諸如缓衝劑、抗微生物劑、張力調節及黏度調節劑）組合。典型經皮以及透皮調配物包括習知水性或非劑’例如乳膏、軟膏、洗劑或糊劑，或呈加藥硬膏劑、= 組合物較佳呈單位劑型，例如錠劑、膠囊或計量溶膠劑量以致患者可投與單次劑量。氧當然，達成治療效果所需之各活性劑的量將隨特定性、投藥途徑、所治療之個體以及所治療之特定病而變化。 ’取疾本發明之化合物、鹽以及/或醫藥組合物亦可與另一仏療活性劑組合使用，例如β2腎上腺素受體促效劑^疒= 劑、抗過敏劑、、消炎劑、免疫抑制劑或抗感染劑。“驗當然，達成治療效果所需之各活性劑的量將隨性、投藥途徑、所治療之麵以及所治療之敎病症^疾 201031663 、病而變化。活性成份可每天投與1至6次，此足以展現所需活性。活性成份較佳每天投與一或兩次，最佳為每日一次。可與PDE4抑制劑組合之適合β2促效劑的實例為硫酸特布他林（terbutaline sulphate )、反丁烯二酸福莫特羅 (eformoterol fumarate)、反丁烯二酸福莫特羅（formoterol fumarate )、班布特羅(bambuterol )、鹽酸丙卡特羅 ❹ （Procaterol hydrochloride )、鹽酸斯本納特（sibenadet hydrochloride )、鹽酸馬布特羅（mabuterol hydrochloride )、硫酸沙丁胺醇（albuterol sulphate )、硫酸沙丁胺醇 (salbutamol sulphate )、羥萘曱酸沙美特羅（saimeter〇i xinafoate )、鹽酸卡莫特羅（carmoterol hydrochloride )、鹽酸(R)-沙丁胺醇（(R)-albuterol hydrochloride)、鹽酸左旋沙丁胺醇（Levalbuterol hydrochloride );鹽酸左沙丁胺醇 (Levosalbutamol hydrochloride );鹽酸（)-沙丁胺醇 g ( (-)-Salbutamol hydrochloride )、酒石酸(R，R)-福莫特羅 ((R，R)-Formoterol tartrate);酒石酸阿福特羅（Arformoterol tartrate)、硫酸貝多拉君（Bedoradrine sulphate)、吲達卡特羅（Indacaterol )、·鹽酸川丁特羅（Trantinterol hydrochloride)、AZD-3199、GSK-159802 ; GSK-597901、 GSK-678007、GSK-642444 ; GSK-961081; AR-C98955AA、鹽酸米維特羅（Milveterol hydrochloride)、BI-1744-CL 以及國際專利中請案第 WO2007/124898號、第 WO2006/122788A1 號、第 W02008/046598 號以及第 51 201031663 W02008095720號中所述之化合物。：可與PDE4抑制劑組合之適合皮質類固醇以及糖皮質 ‘ 激素（glucocorticoid)的實例為潑尼龍（prednisolone)、甲潑尼龍（甲基prednisolone )、*** (dexamethasone )、***麟酸鋼（dexamethasone cipecilate )、茶非可特（naflocort)、地夫可特（deflazacort)、乙酸鹵潑尼松（halopredone acetate )、布*** (budesonide )、二丙酸倍氯米松（beclomethasone ❿ dipropionate )、氫皮質酮（hydrocortisone )、曲安奈德 (triamcinolone acetonide )、I 輕松（fluocinolone acetonide)、醋酸氟輕松（fluocinonide)、特戊酸氯可托龍 (clocortolone pivalate )、醋丙甲潑尼龍（甲基 prednisolone aceponate )、棕櫚酸地塞来松（dexamethasone palmitoate )、替潑尼旦（tipredane )、醋丙氫皮質酮（hydrocortisone aceponate )、潑尼卡醋（prednicarbate )、二丙酸阿氯米松 (alclometasone dipropionate )、鹵米松（halometasone )、石黃庚曱潑尼龍（曱基prednisolone suleptanate)、糠酸莫美他松（mometasone furoate)、利美索龍（rimexolone)、法呢酸潑尼龍（prednisolone farnesylate )、環索奈德 (ciclesonide )、丙酸布替可特（butixocort propionate )、 RPR-106541、丙酸地潑羅酮（deprodone propionate)、丙酸氟替卡松（fluticasone propionate )、糠酸氟替卡松 (fluticasone furoate )、丙酸鹵倍他索（halobetasol propionate)、氣替潑諾（loteprednoletabonate)、丁酸丙酸 52 201031663 * 倍他米松（betamethasone butyrate propionate)、氟尼縮松 V» (flunisolide )、潑尼松（prednisone )、***填酸鈉 (dexamethasone sodium phosphate )、曲安西龍 (triamcinolone )、17-戊酸倍他米松（betamethasone 17-valerate )、倍他求松（betamethasone )、二丙酸倍他来松（betamethasone dipropionate )、乙酸氫皮質酮 (hydrocortisone acetate )、氩皮質酮丁二酸納 ❹ （hydrocortisone sodium succinate )、潑尼龍填酸納 (prednisolone sodium phosphate )以及丙丁酸氫皮質酮 (hydrocortisone probutate)。可與PDE4抑制劑組合之適合M3拮抗劑（抗膽鹼劑）的實例為嗟托錄（tiotropium)鹽、氧托按（oxitropium) 鹽、氟托銨（flutropium)鹽、異丙托銨（ipratropium)鹽、格隆錄（glycopyrronium)鹽、曲司銨（trospium)鹽、瑞伐托酯（revatropate)、艾帕托酯（eSpatr〇pate)、3-[2-羥基 _ _2,2-雙(2-噻吩基）乙醯氧基]_1_(3_苯氧基丙基)_ι_氮鏽雙環 [2.2.2]辛烧鹽（尤其阿地銨（狀1丨出11丨11111)鹽，更佳為阿地溴録（aclidinium bromide))、1·(2-苯乙基)-3-(9H_ -9- 基羰氧基)-1-氮鏽雙環[2.2.2]辛烷鹽、2-侧氧基-1,2,3,4-四氫喹唾啉-3-曱酸内-8-曱基-8-氮雜雙環[3.2.1]辛各基酯鹽 (DAU-5884)、3-(4-苯甲基旅嗓_1_基)_1_環丁基小經基+ 苯基丙-2-酮（NPC-14695)、N-[l-(6-胺基吼咬-2-基甲基） 0辰咬-4_基]-2(R)-[3,3-二氟-1(R)_環戊基]-2_羥基_2_苯基乙醯胺（J_104135)、2⑻-環戊基-2-羥基-N-[1-[4(S)-曱基己基] 53 201031663 哌啶-4-基]-2-苯基乙醯胺（J-106366)、2(R)-環戊基-2-羥基 -N-[l-(4-甲基-3-戊烯基）-4-哌啶基]-2-苯基乙醯胺 (J-104129 )、1-[4-(2-胺基乙基)哌啶-1-基]-2(R)-[3,3-二氟環戊-1(R)-基]-2-經基-2-苯基乙-1-酮（Banyu-280634 )、 Ν-[Ν-[2-[Ν·[1-(環己基曱基)哌啶-3(R)-基曱基]胺曱醯基] 乙基]胺甲醯基曱基]-3,3,3-三苯基丙醯胺（BanyuCPTP)、 2(R)-環戊基-2-羥基-2-苯基乙酸4-(3-氮雜雙環[3.1.0]己-3-基)-2-丁炔酯（Ranbaxy 364057)、UCB-101333、默克公司 (Merck)之〇rM3、7-内_(2_羥基·2,2-二苯基乙醯氧基)-9,9-二曱基-3-氧雜-9-氮鏽三環[3.3·1.0(2,4)]壬烷鹽、7-(2,2-二苯基丙醯氧基）-7,9,9-三甲基-3-氧雜-9-氮鏽三環 [3·3.1·0*2,4*]壬烷鹽、7-羥基-7,9,9-三甲基-3·氧雜-9-氮鑌三環[3.3.1.0*2,4*]壬烷9-甲基-姐-苐-9-曱酸酯鹽，其全部均視情況呈其外消旋體、其對映異構體、其非對映異構體以及其混合物之形式，且視情況呈其藥理相容性酸加成鹽之形式。在所述鹽中，氯化物、溴化物、破化物以及曱續酸鹽為較佳。可與PDE4抑制劑組合之適合抗過敏劑的實例為抗組織胺劑（例如美沙σ比林（Methapyrilene )、曱喧吩嗓 (Mequitazine )、鹽酸氮拉斯汀（Azelastine hydrochloride)、阿伐斯丁（ Acrivastine )、反丁烯二酸氫依美斯汀 (Emedastine difumarate );反丁烯二酸依美斯汀（Emedastine fumarate )、洛拉他定（Loratadine )、鹽酸赛庚咬 (Cyproheptadine hydrochloride )、鹽酸苯海拉明 54 201031663 ( Diphenhydr 胺 hydrochloride )、鹽酸多塞平（Doxepin hydrochloride )、鹽酸普敏太定（Promethazine hydrochloride )、鹽酸左卡巴斯汀（Levocabastine hydrochloride )、地氣雷他定（Desloratadine )、桂利嗪 (Cinnarizine )、鹽酸司他斯汀（Setastine hydrochloride )、咪吐斯汀（Mizolastine )、依巴斯:?丁（ Ebastine)、鹽酸西替利嗓（Cetirizine hydrochloride )、鹽酸依匹斯 '汀（Epinastine 〇 hydrochloride )、鹽酸奥洛他定（Olopatadine hydrochloride)、苯績酸貝他斯汀（Bepotastine besilate )、鹽酸曲普立定（Triprolidine hydrochloride)、反丁烯二酸盧帕他定（Rupatadine fumarate )、鹽酸菲索特非那定 (Fexofenadine hydrochloride )、二鹽酸左西替利嘻 (Levocetirizine dihydrochloride)、酮替芬（Ketotifen)、順丁烯二酸派σ比庚咬（Azatadine maleate )、順丁稀二酸二曱茚定（Dimethindene maleate )、反丁烯二酸氯馬斯汀 ◎ (Clemastine fumarate)、阿卡他定（Alcaftadine)、比拉斯汀（Bilastine )、鹽酸伐匹他定（Vapitadine hydrochloride )、 AZD-1744、GSK-1004723D、GSK-835726、SUN-1334H)、 CRTH拮抗劑（例如雷馬曲班（Ramatroban)、AMG-009、 OC-000459 )或肥大細胞穩定劑（例如奈多羅米 (nedocromil)、〇比癌司特鉀（pemirolast potassium)、色甘酸鈉（chromoglycate sodium )、甲磺司特（suplatast tosilate))。其他可能組合包含例如包括PDE4抑制劑與另一消炎 55 201031663 劑之組合’所述肩炎劑堵如非類固醇消炎藥（n〇n_ster〇idal anti-inflammatory drug; NS AID )’ 諸如白三烯（leukotriene ) 拮抗劑（例如異丁司特（Ibudilast )、水合普魯司特 (Pmnlukast hydrate )、紮魯司特（ZafMukast)、孟魯司特 (Montelukast)、泰魯司特（Tipelukast))、FLAp 抑制劑、脂肪加氧酶抑制劑、環加氧酶抑制劑（例如雙氣芬酸 (diclofenac )、布洛芬（ibuprofen )、塞内昔布（celecoxib )); 彈性蛋白酶抑制劑、Syk激酶抑制劑、ρΐ3Κδγ抑制劑或另一 PDE抑制劑（例如茶鹼（the〇phylline ))。可與PDE4抑制劑組合之適合免疫抑制劑的實例為匹克莫司（picremolimus)、他克莫司（tacromilus)、環孢黴素 A (cyclosporine A)、來氟米特（ieflunomide)、甲胺喋呤（methotrexate)、抗TNF藥劑以及國際專利申請案第 W02009021696號以及第W02008/077639號中所述之化合物。〇可與PDE4抑制劑組合之適合抗感染劑的實例為莫匹羅星（mupiricin )、瑞他莫林（retapamulin )、克黴唑 (clotrimazole )、綱康唆（ketoconazole )以及特比英芬 (terbinafine ) ° 可與PDE4抑制劑組合之適合Syk激酶抑制劑的實例為佛伐替尼（fosfamatinib )(來自 Rigel)、R-348 (來自In the p-director (for example EP 0505321, WO 92/04068 and WO 92/04928); or measuring sliders, such as Genuine_ (formerly known as Novolizer SD2FL), which are described in the following patent application: W097/000703 No., No. W003/000325 and No. W003/061742. Reproducible dose measurement is one of the primary concerns of multi-dose inhaler devices. Powder formulations must exhibit good and stable flow properties because the filling of the dose measuring cup or cavity is primarily affected by gravity. 47 201031663 'For reloading the order: the domain volume reduction device The measurement accuracy and reproducibility can be ensured by the manufacturer. — _ ^ — 10,000 faces, winter swords have a higher number of doses, however - generally reduce the filling dose test = multiple suction air flow usually goes straight through the dose I test chamber and because of the large system of suction It is not possible to draw in the air flow _, so the volume is measured and the number of g junctions is obtained during the discharge. It is easy to remove the powder from the cavity. Therefore, an independent disintegration member is necessary. However, it is always part of the inhaler design. Because of the multiple doses: eight quantities, it is necessary to make the inner wall of the air duct and the force of the force = 1: 'can be used, clean these parts, and = the straight balance of the $. - Some multi-dose inhalers' can be taken after a prescribed number of doses have been taken. In the case of a drug having a disposable drug container, the inhalation is prevented from being administered via a dry powder inhaler, and the present invention is controlled by the use of a gas propellant or by means of Under the hobbies (four) twist w ", the thief to see the fine mist. The advantages of these sprayers in ===: refer to its content. In the second gift of the fine number 7, this article is used to pass the suction to the local to The spray of the lungs can be adjusted, for example, by the use of a liquid or a suspension, or by a suitable liquefied propellant, by means of a suitable liquefied propellant, such as a fixed dose of 11). The compound can be a suspension or a solution and generally contains an active ingredient and a developer of human I» such as a gas carbide or a chlorofluorocarbon containing cerium or a mixture thereof, which is a hydrofluorocarbon. For example, dichlorodifluoromethane, trichlorofluoromethane, tetrafluoroethylene bromide, especially mi tetrafluoroethylene bromide, mm, heptahydrate, or its compound. Carbon dioxide or other suitable gas can also use gas. , ^ compound can be without _ or kemu age with this technology compounding agent, such as surfactants (such as oleic acid or valve two agents (such as ethanol). The pressurized formulation is generally stored in a can: two holes (closed) and is matched with an actuator equipped with a mouthpiece to be used to inhale the rice. When inhaling the secret, the ruler ^ ί. In order to achieve such particle size, can be separated by conventional means = as follows: edge: or sieved to separate. The particles will preferably be crystalline: 难以 difficult to achieve good Fluidity and extreme coalescence tendency should be larger in the inhaler, but in the case of granules, therefore, use such as lactose or glucose in the month. The particle size of the excipient is usually - large milk 49 201031663 sugar 'It will usually be supplied in the form of ground lactose, preferably crystalline alpha monohydrate lactose. σ The pressurized aerosol composition will typically be filled into a canister equipped with a valve (especially a metering valve). There are plastic materials, such as the fluorocarbon polymers described in WO 96/32150. The cans are mated with an actuator suitable for intra-cheek delivery. Typical compositions for nasal delivery include the above-described compositions for inhalation. And further comprising a solution or suspension present in an inert vehicle such as water a form of non-pressurized composition, optionally in combination with conventional excipients (such as buffers, antimicrobials, tonicity modifiers, and viscosity modifiers) that can be administered by nasal pump. Typical transdermal and transdermal formulations Including conventional aqueous or non-agents such as creams, ointments, lotions or pastes, or as medicated plasters, = compositions are preferably in unit dosage form, such as lozenges, capsules or metered sol doses such that the patient can be administered Single dose. Oxygen, of course, the amount of each active agent required to achieve a therapeutic effect will vary with the particularity, route of administration, the individual being treated, and the particular condition being treated. 'The compound, salt, and/or Alternatively, the pharmaceutical composition may be combined with another therapeutically active agent, such as a beta 2 adrenergic receptor agonist, an anti-allergic agent, an anti-inflammatory agent, an immunosuppressive agent or an anti-infective agent. "Of course, the amount of each active agent required to achieve a therapeutic effect will vary with the nature, the route of administration, the surface to be treated, and the condition of the disease to be treated, 201031663. The active ingredient can be administered 1 to 6 times a day. This is sufficient to demonstrate the desired activity. The active ingredient is preferably administered once or twice daily, preferably once daily. An example of a suitable beta 2 agonist that can be combined with a PDE4 inhibitor is terbutaline sulphate. ), eformoterol fumarate, formoterol fumarate, bambuterol, Procaterol hydrochloride, hydrochloric acid Sibenadet hydrochloride, mabuterol hydrochloride, albuterol sulphate, salbutamol sulphate, saimeter〇i xinafoate, cammot hydrochloride Carmoterol hydrochloride, (R)-albuterol hydrochloride, levobuterol hydrochlori De ); Levosalbutamol hydrochloride; hydrochloric acid ()-salbutamol hydrochloride (G), tartaric acid (R, R)-formoterol (R(R)-Formoterol tartrate); tartaric acid Arformoterol tartrate, Bedadordrine sulphate, Indacaterol, Trantinterol hydrochloride, AZD-3199, GSK-159802; GSK-597901, GSK-678007 , GSK-961044; GSK-961081; AR-C98955AA, Milveterol hydrochloride, BI-1744-CL, and International Patent Application No. WO2007/124898, WO2006/122788A1, No. WO2008/046598 And the compound described in No. 51 201031663 W02008095720. Examples of suitable corticosteroids and glucocorticoids that can be combined with PDE4 inhibitors are prednisolone, methylprednisolone, dexamethasone, dexamethasone, and dexamethasone (dexamethasone cipecilate), naflocort, deflazacort, halopredone acetate, budesonide, beclomethasone ❿ dipropionate, Hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate, acetophenone methylprednisolone (methyl prednisolone) Aceponate ), dexamethasone palmitoate, tipredane, hydrocortisone aceponate, prednicarbate, alclometasone dipropionate , halomethasone, sulphate, and nylon (prednisolone su) Leptanate), mometasone furoate, rimexolone, prednisolone farnesylate, ciclesonide, butixocort propionate , RPR-106541, deprodone propionate, fluticasone propionate, fluticasone furoate, halobetasol propionate, loteprednoletabonate Butyrate propionic acid 52 201031663 * Betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone Triamcinolone ), betamethasone 17-valerate, betamethasone, betamethasone dipropionate, hydrocortisone acetate, arson corticosterone Hydrocortisone sodium succinate, prednisolone sodium phosphate, and Acid hydrogen corticosterone (hydrocortisone probutate). Examples of suitable M3 antagonists (anticholinergic agents) which may be combined with PDE4 inhibitors are tiotropium salts, oxitropium salts, flutropium salts, ipratropium Salt, glycopyrronium salt, trastium salt, revatropate, espatr〇ate, 3-[2-hydroxy__2,2-double ( 2-thienyl)ethyloxy]_1_(3_phenoxypropyl)_ι_nitrogen bicyclo[2.2.2]octane salt (especially adipic acid (like 1 丨 11丨11111) salt, more Aclidinium bromide, 1(2-phenylethyl)-3-(9H_-9-ylcarbonyloxy)-1-nitrogenbicyclo[2.2.2]octane salt, 2 -Sideoxy-1,2,3,4-tetrahydroquinoxalin-3-decanoic acid-8-indenyl-8-azabicyclo[3.2.1]octyl ester (DAU-5884) , 3-(4-Benzylmethyl 嗓_1_yl)_1_cyclobutyl sulfhydryl + phenylpropan-2-one (NPC-14695), N-[l-(6-amino benzoate) -2-ylmethyl) 0-biting-4_yl]-2(R)-[3,3-difluoro-1(R)-cyclopentyl]-2-hydroxy-2-phenylacetamide (J_104135), 2(8)-cyclopentyl-2-hydroxy-N-[1-[4(S)-decylhexyl] 53 201031663 piperidin-4-yl]-2-phenyl Amine (J-106366), 2(R)-cyclopentyl-2-hydroxy-N-[l-(4-methyl-3-pentenyl)-4-piperidinyl]-2-phenyl Indoleamine (J-104129), 1-[4-(2-Aminoethyl)piperidin-1-yl]-2(R)-[3,3-difluorocyclopenta-1(R)-yl ]-2-Phenyl-2-phenylethan-1-one (Banyu-280634), Ν-[Ν-[2-[Ν·[1-(cyclohexylfluorenyl)piperidin-3(R)- Alkylamino]amino]aminocarbamimidyl]-3,3,3-triphenylpropanamide (BanyuCPTP), 2(R)-cyclopentyl-2-hydroxy-2 -Phenylacetic acid 4-(3-azabicyclo[3.1.0]hex-3-yl)-2-butynyl ester (Ranbaxy 364057), UCB-101333, Merck (Merck) 〇rM3, 7- _(2_hydroxy·2,2-diphenylethenyloxy)-9,9-diamidino-3-oxa-9-nitrogen tricyclo[3.3.1.0(2,4)]壬Alkane salt, 7-(2,2-diphenylpropenyloxy)-7,9,9-trimethyl-3-oxa-9-nitrogen tricyclic [3·3.1·0*2,4 *]decane salt, 7-hydroxy-7,9,9-trimethyl-3.oxa-9-azinium tricyclo[3.3.1.0*2,4*]decane 9-methyl-sister-苐-9-phthalate salt, all of which are in the form of their racemates, their enantiomers, their diastereomers, and mixtures thereof, and, where appropriate, their pharmacological compatibility Acid addition salt Form. Among the salts, chlorides, bromides, broken compounds and sulfonate are preferred. Examples of suitable anti-allergic agents that can be combined with PDE4 inhibitors are antihistamines (e.g., Methapyrilene, Mequitazine, Azelastine hydrochloride, Avastin). (Acrivastine), Emedastine difumarate; Emedastine fumarate, Loratadine, Cyproheptadine hydrochloride, Diphenhydramine hydrochloride 54 201031663 (Diphenhydramine hydrochloride), Doxepin hydrochloride, Promethazine hydrochloride, Levocabastine hydrochloride, Desloratadine , Cinnarizine, Setastine hydrochloride, Mizolastine, Ebastine, Cetirizine hydrochloride, Epic Hydrochloride 'Epinastine 〇hydrochloride, Olopatadine hydrochloride, Benazin benzoate (Bepota) Stine besilate ), Triprolidine hydrochloride, Rupatadine fumarate, Fexofenadine hydrochloride, Levocetirizine dihydrochloride , Ketotifen, Azatadine maleate, Dimethindene maleate, Clemastine fumarate ), Alcaftadine, Bilastine, Vapitadine hydrochloride, AZD-1744, GSK-1004723D, GSK-835726, SUN-1334H), CRTH antagonists (eg Ramatroban, AMG-009, OC-000459) or mast cell stabilizers (eg, nedocromil, pemirolast potassium, chromoglycate sodium, A) Suplatast tosilate). Other possible combinations include, for example, a combination of a PDE4 inhibitor and another anti-inflammatory 55 201031663 agent, such as a non-steroidal anti-inflammatory drug (NS AID ), such as leukotrienes (such as leucotrienes). Leukotriene antagonists (eg Ibudilast, Pmnlukast hydrate, ZafMukast, Montelukast, Tipelukast), FLAp Inhibitors, lipoxygenase inhibitors, cyclooxygenase inhibitors (eg, diclofenac, ibuprofen, celecoxib); elastase inhibitors, Syk kinase inhibition Agent, ρΐ3Κδγ inhibitor or another PDE inhibitor (such as the phylline). Examples of suitable immunosuppressive agents which can be combined with PDE4 inhibitors are picremolimus, tacromilus, cyclosporine A, etflunomide, methotrexate Meth (methotrexate), an anti-TNF agent, and a compound described in International Patent Application No. WO20091696696 and WO2008/077639. Examples of suitable anti-infective agents that can be combined with PDE4 inhibitors are mupiricin, retapamulin, clatumrimazole, ketoconazole, and terbiprofen ( Terbinafine ) ° Examples of suitable Syk kinase inhibitors that can be combined with PDE4 inhibitors are fosfamatinib (from Rigel), R-348 (from

Rigel)、R-343 (來自 Rigel)、R_112 (來自 Rigel)、白皮杉醇（piceatannol)、2-(2-胺基乙胺基)-4-[3-(三氟甲基)苯基胺基]嘧啶-5-甲醯胺、R_〇9i (來自Rigel)、6_^氣 201031663 ' -2-(3,4,5-三甲氧基苯基胺基）癌唆_4-基胺基]-2,2-二甲基 m -3,4_二氩-2H-吼啶並[3,2-b][l,4]噁嗪-3-酮苯磺酸酯 (R-406，來自Rigel)、1-(2,4,6-三羥基苯基)-2-(4-甲氧基笨基）乙-1-酮、N-[4_[6-(環丁基胺基)-9H-嗓呤-2-基胺基]笨基]-N-甲基乙醯胺（QAB-205，來自 Novartis)、2-[7-(3,4-二甲氧基苯基)咪唑並[l,2_c]嘧啶-5-基胺基]吡啶-3-甲醯胺二鹽酸鹽（BAY-61-3606，來自 Bayer)以及 AVE-0950 (來 ® 自 Sanof卜Aventis)。可與TOE4抑制劑組合之適合Π3κδγ抑制劑的實例為 2-曱基-2-[4-[3-甲基-2-側氧基冬(3-喹啉基)-2,3-二氫-1Η- 咪唆並[4,5-c]喹啉-1-基]苯基]丙腈（ΒΕΖ_235，來自Rigel), R-343 (from Rigel), R_112 (from Rigel), piceatannol, 2-(2-aminoethylamino)-4-[3-(trifluoromethyl)phenyl Amino]pyrimidine-5-formamide, R_〇9i (from Rigel), 6_^gas 201031663 '-2-(3,4,5-trimethoxyphenylamino) carcinoma 唆4-amine -2,2-dimethyl m -3,4_di-argon-2H-acridino[3,2-b][l,4]oxazin-3-one benzenesulfonate (R-406 From Rigel), 1-(2,4,6-trihydroxyphenyl)-2-(4-methoxyphenyl)ethan-1-one, N-[4_[6-(cyclobutylamino) )-9H-indol-2-ylamino]phenyl]-N-methylacetamide (QAB-205 from Novartis), 2-[7-(3,4-dimethoxyphenyl) Imidazo[l,2_c]pyrimidin-5-ylamino]pyridine-3-carboxamide dihydrochloride (BAY-61-3606 from Bayer) and AVE-0950 (from ® Sanof Aventis). An example of a suitable Π3κδγ inhibitor that can be combined with a TOE4 inhibitor is 2-mercapto-2-[4-[3-methyl-2-oxo-oxy(3-quinolinyl)-2,3-dihydro -1Η-imidol[4,5-c]quinolin-1-yl]phenyl]propanenitrile (ΒΕΖ_235, from

Novartis)、CAL-101 (來自 Calistoga Pharmaceuticals)以及N-乙基-:^’發⑽力-王甲氧基苯基胺基彡吡啶並似仲比唤-6-基]硫脲（AEZS-126，來自 AeternaZentaris)。本發明之尤其較佳醫藥組合物包括式（〗）之鹽以及治參療有效量之一或多種由以下所構成的族群中選出之其他治療劑.糠酸莫美他松、環索奈德、布***、丙酸氟替卡松、糠酸氟替卡松、戊酸倍他米松（betamethas〇ne valerate)、丙酸氣倍他索（clobetas〇1 pr〇pi〇nate)、嘆托銨鹽、格隆銨（glycopymmium)鹽、3_[2_經基_2,2_雙(2_嗟吩基）乙醯氧基]-1-(3-苯氧基丙基；)_；[_氮鏽雙環[222]辛烷鹽（尤其阿地铵鹽，較佳為阿地溴銨）、苯乙美 Η -9-基幾氧基)·1·氮鏽雙環[2.2.2]辛燒鹽、^莫特 (fomioterol)、沙美特羅（salmeter〇1)、吲達卡特羅、'卡莫 57 201031663 特羅（cannoterol)、國際專利申請案第w〇2〇〇9/〇2l696號以及第W02008/077639射所述之化合物、美沙吼林、西替利嗪（cetirizine)、洛拉他定、依巴斯$丁、地氯雷他定、非索非較（fexofenadine)、氮拉斯 (azdastine)、左卡巴斯、汀（le—)、奥洛他定（〇1〇patadine)、孟魯司 ^ 克莫司、他克莫司、莫匹羅星、瑞他莫林、克黴嗤、酮康唑、特比萘芬。 ❹ 因此，在本發明之-態樣中，組合物包括式⑴化合質類轉。尤其難皮魏_為錄酸莫美他 Ϊ酸、布***、糠酸氟替卡松、丙酸氟替卡松、及丙酸氣倍他索所構成的族群中選出之皮及之/ —態樣中，組合物包括式⑴化合物以二抗膽驗劑為㈣托錢鹽、格隆銨鹽、 ❹ 二ί 及“(2_苯乙基)-3_(9H——9-基 ίίΐΓϋ雙環[2.2.2㈣鹽所構成的族种選出之组合物可進—步包括由 = 族群中選出之皮質類固醇。“及丙酉夂氟替卡松所構成的及合崎，組合物包括式⑴化合物以沙美特羅、猶卡特羅 /補為“莫特羅、 WO2007/124898 /莫特羅以及國際專利申請案第現、弟 WO2006/122788A1 號、第 58 201031663 ：=1_46598號以及第W⑽_9572G財所述 =所構成的族群中選出之p2促效劑。組合物可進—井J 糠酸莫美他松、環索奈德、布*** = 及丙酸氟替卡松所構成的族群中選出之皮;=卡=以發明之鹽以及β2促效齡，組合物由:本 ❹外氮鏽雙環[2·2.2]辛燒鹽以及1你苯乙基)-3_(9H- -9-基幾氧基Η-氮鑌雙環r2 本乙成的族群中選出之抗膽驗劑。 · ·]辛燒鹽所構声以=1月卜之式⑴化合物以及組合可用於治療呼吸由膚以及發火性疾病，其中預期使用p :斗及、皮 :，所述疾病例如哮喘、慢性阻塞性肺病有利發=:節炎、多發性硬化症、異位性皮膚炎、 • j或在欲用於藉:^::t中共同投序投與之不同組合物中投與。问蚪、伴隨或依者 -預極接近地投舆。或稍晚的__。或在另—方=他活性劑在一天中曰服用兩次而其他活性兩種活性劑可每藥t之一次同時進行，或分人其與每日兩次給所有活性劑將同時服用。較。較佳至少兩種且更佳將以混合物形式投與。夕兩種且更佳所有活性劑 59 201031663 本發明之活性物質組合物較佳以利用吸入器（尤其乾 f 粉吸入器）傳遞之吸入用組合物的形式投與；然而，任何 -其他形成之經鼻、局部、非經腸或經口施用均有可能。本文中，施用吸入型組合物體現較佳施用形式，尤其在阻塞性肺病之療法或哮喘治療中。其他適用於本發明之活性鹽之調配物的載劑可見於Novartis), CAL-101 (from Calistoga Pharmaceuticals) and N-ethyl-:^' hair (10) force-wang methoxyphenylaminopyridinium pyridine and carbaryl--6-yl]thiourea (AEZS-126 From AeternaZentaris). Particularly preferred pharmaceutical compositions of the present invention comprise a salt of formula ()) and a therapeutically effective amount of one or more other therapeutic agents selected from the group consisting of: mometasone furoate, ciclesonide , budesonide, fluticasone propionate, fluticasone furoate, betamethas〇ne valerate, clobetas〇1 pr〇pi〇nate, sulphate ammonium, glycopyammonium (glycopymmium) salt, 3_[2_carbyl-2,2_bis(2_nonyl)ethoxycarbonyl]-1-(3-phenoxypropyl;)_;[_nitrogen bicyclo[ 222] octane salt (especially adipic ammonium salt, preferably adiponium bromide), phenethyl hydrazine -9-yl oxyl) · 1 · nitrogen rust bicyclo [2.2.2] octane salt, ^ Mo Fomioterol, salmeter〇1, 吲达卡特罗, '卡莫57 201031663 cannoterol, international patent application number w〇2〇〇9/〇2l696 and W02008/077639 The compound, methicillin, cetirizine, lolatazidine, ebabadine, desloratadine, fexofenadine, azdastine, Left Kabas Ting (le-), olopatadine (〇1〇patadine), monteluk^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Naphthene. ❹ Therefore, in the aspect of the invention, the composition comprises a compound of the formula (1). In particular, the skins selected from the group consisting of emodic acid, dexamethasone, fluticasone citrate, fluticasone propionate, and propidium propionate are also selected. The compound comprising the compound of the formula (1) is a secondary anti-cholinergic agent (IV), a tonic salt, a glycopyrronium salt, a ruthenium salt and a "(2_phenethyl)-3_(9H-9-yl ίίΐΓϋbicyclo[2.2.2(tetra)) salt. The selected composition of the selected species may further comprise a corticosteroid selected from the group of = "and a combination of fluticasone and hydrazine, the composition comprising the compound of formula (1) to salmeterol, jucatalo / Compiled as "Pot2, selected from the group consisting of Motello, WO2007/124898/Motro, and the international patent application, the current WO2006/122788A1, the 58th 201031663:=1_46598, and the W(10)_9572G An agonist. The composition can be selected from the group consisting of well J, mometasone furoate, ciclesonide, budesonide = and fluticasone propionate; = card = promoted by the salt of the invention and β2 Age, the composition consists of: Nitrogen rust double ring [2·2.2] octyl salt and 1 benzene Ethyl)-3_(9H- -9-yl-methoxy-hydrazinium-azaindole bi-ring r2 The anti-cholinergic agent selected from the group of B-forms. · ·] The sound of Xin Shaoyan is 1 month (1) Compounds and combinations can be used for the treatment of respiratory and inflammatory diseases, wherein it is expected to use p: bucket and skin: the diseases such as asthma, chronic obstructive pulmonary disease are favorable =: phlegm, multiple sclerosis, ectopic Sexual dermatitis, • j or in a different composition that is intended to be used for borrowing: ^::t in a co-injection order. Ask, companion, or dependent-pre-polarly close to cast. Or later __. Or in another side = his active agent is taken twice a day while the other active two active agents can be administered simultaneously for each dose of t, or it can be administered simultaneously with all active agents twice daily. Preferably, at least two and more preferably will be administered as a mixture. Two and more preferably all active agents 59 201031663 The active substance composition of the present invention preferably utilizes an inhaler (especially a dry powder inhaler) Delivery in the form of a composition for inhalation; however, any-other formed nasal, local, non- Intestinal or oral administration is possible. Herein, administration of the inhaled composition embodies a preferred form of administration, especially in the treatment of obstructive pulmonary disease or asthma. Other carriers suitable for the formulation of the active salt of the present invention may be used. Seen at

Remington. The Science and Practice of Pharmacy,第 20 版 Lippincott Williams & Wilkins，Philadelphia, Pa” 2000 中。 ❹ 以下非限制性實例說明本發明之代表性醫藥組合物。當使用活性劑之組合時，預期所有活性劑均將同時或柃間上極接近地投與。或者，一或兩種活性劑可在上午服用而其他活性劑在-天中稍晚的時候服用。或在另一方案中，一或兩種活性劑可每曰服用兩次而其他活性劑每曰服用一，，其與每日兩次給藥中之一次同時進行，或分開進行。較佳至少兩種且更佳所有活性劑將同時服用。較佳至少兩種且更佳所有活性劑將以混合物形式投與。引用以下製劑形式作為調配物實例：參組合物實例1 根據以下配方製備50,000個各含有1〇〇毫克 3-((/-(3,5-二氣吡啶冰基胺基)小經基_8,8_二曱基_6,7,8,9- 四氫3H—比嗤並[3,4_c]異嘻琳冬基)甲基)苯甲酸甲醋（活性成份）之膠橐： 3性成份一留 T> A Jpd: ------- 5公斤 L·^：水合礼糖 10公斤 201031663Remington. The Science and Practice of Pharmacy, 20th edition Lippincott Williams & Wilkins, Philadelphia, Pa" 2000. ❹ The following non-limiting examples illustrate representative pharmaceutical compositions of the invention. When using a combination of active agents, it is expected All active agents will be administered at the same time or in close proximity to each other. Alternatively, one or two active agents may be taken in the morning while the other active agent is taken later in the day - or in another regimen, Or two active agents may be taken twice per sputum and the other active agent may be taken once per sputum, simultaneously with one of the two daily administrations, or separately. Preferably at least two and more preferably all active agents It will be taken at the same time. Preferably at least two and more preferably all of the active agents will be administered as a mixture. The following formulation forms are cited as examples of formulations: Reference Example 1 Preparation of 50,000 each containing 1 mg of 3- according to the following formulation ((/-(3,5-dipyridyl ylylamino) small via) _8,8-dimercapto_6,7,8,9-tetrahydro 3H-specific oxime [3,4_c]嘻琳冬基) methyl) benzoic acid methyl vinegar (active ingredient) glue : 3 of the components a left T > A Jpd: ------- 5 kilograms L · ^: 10 kg of hydrated glucose 201031663 Eli

% Λ 程序且裝載至合適之混經由60篩目篩將上述成份過篩合器中並填充至50,〇〇〇個明膠膠嚢中組合物實例2% Λ Procedure and loading to a suitable mix. Pass the above ingredients through a 60 mesh screen and fill to 50, in a gelatin capsule. Composition Example 2

由以下配方製備50，_個各含有5〇毫克一乳吼唆冰基胺基經基_8,8-二甲基-6,7,8,9-四氫3Η = [Μ·撕私姻雖甲_ (活性成份）·Prepared from the following formula 50, each containing 5 〇 mg of a chylolyl-based amino group via _8,8-dimethyl-6,7,8,9-tetrahydro 3 Η = [Μ· Although A_ (active ingredient)·

使所有粉末均通過孔徑為〇 6 之混合器中混合2〇分鐘且使用9亳米/、、師，心後在合適 (bevelled punch)壓縮為3〇〇毫克^盤狀平垣的斜刀凸模時間為約3分鐘。齊丨所述竣劑之崩解【圖式簡單說明】無 201031663 【主要元件符號說明】無Allow all powders to pass through a mixer with a pore size of 〇6 for 2 〇 minutes and use 9 /m/, 师, after the heart is compressed in a suitable (bevelled punch) to 3 〇〇 mg ^ disc-shaped flat cymbal punch The time is about 3 minutes. Disintegration of the tincture of Qi Qi [Simple description of the map] None 201031663 [Description of main components] None

Claims

201031663 會 1201031663 meeting 1

七、申請專利範圍：Seven, the scope of application for patents:

5 =經基以及胺基所構成的族群中選出，芳基、c 2 ((MIC(〇)NRaRb 基團、Cl-4 烧基-C5-1〇員含* G貝含芳基、Cl·4烧基_5至10 只3 Ν雜ί哀基、磺醯基婪复Φ撕、η 基^酿基-〜烧基，由二方土、雜芳基以及雜環基視情況經—或多個5 = selected from the group consisting of a group and an amine group, an aryl group, c 2 ((MIC(〇)NRaRb group, Cl-4 alkyl group-C5-1 member containing * G shell containing an aryl group, Cl· 4 burnt base _5 to 10 only 3 ί ί ί 、, sulfonyl hydrazine Φ Φ tear, η ^ 酿 - ～～～～～～～～～～～～～～～～～～～～ Multiple

的ί群選出之取代基取代:U基、C- 基：素原子、三氣甲基、絲、Cl-鄭姆俩基々4絲、氰基、胺甲醯基、玟基團以及-C(〇)NRaRb基團；且 2中aRa以及f獨立地表示氫原子或Cl_4烧基，且 ^ 疋由C5·10芳基以及含有至少一個選自N、S以及Ο 笔原子的5至1〇員雜芳基所構成的族群中選出，其中所 ^基以及所述雜芳基視情況經一或多個選自齒素原子、烷基以及Ci-4烷氧基之取代基取代，或其醫藥學上可接受之鹽或N氧化物。 2.如申請專利範圍第1項所述之化合物，其中R1表 63 201031663 譫 j 示經基。 3.如申請專利範圍第1項或第2項所述之化合物，其中R2表示5原子、Cl'4燒基-C5_10芳基、Cm烧基_5至1〇員含N雜芳基、（V4燒基-5至1〇員含N雜環基，其中所述芳基、雜芳基以及雜環基視情況經-或兩個由c」燒氧基、竣基、CM烧氧餘、氰基以及胺曱醯基所構成的族群選出之取代基取代。、Substituted substituents for the group: U group, C- group: aze atom, trimethyl group, silk, Cl-Zhengm base 4, cyano group, amine mercapto group, fluorenyl group and -C (〇)NRaRb group; and in 2, aRa and f independently represent a hydrogen atom or a Cl_4 alkyl group, and 疋 consists of a C5·10 aryl group and contains at least one selected from N, S and Ο pen atoms 5 to 1 〇 Selected from the group consisting of heteroaryl groups, wherein the substituent and the heteroaryl group are optionally substituted with one or more substituents selected from the group consisting of a dentate atom, an alkyl group, and a Ci-4 alkoxy group, or A pharmaceutically acceptable salt or N-oxide. 2. The compound of claim 1, wherein the R1 table 63 201031663 谵 j shows a meridian. 3. The compound according to claim 1 or 2, wherein R2 represents 5 atoms, Cl'4 alkyl-C5_10 aryl, Cm alkyl _5 to 1 含 N-heteroaryl, The V4 alkyl group - 5 to 1 member contains an N heterocyclic group, wherein the aryl group, the heteroaryl group and the heterocyclic group are optionally subjected to - or two by a c" alkoxy group, a thiol group, a CM group, and an oxygen group. Substituted by a group selected by a group consisting of a cyano group and an amine fluorenyl group.

4.如申请專利範圍第3項所述之化合物，其中R2表示氫原子、CM絲_苯基，其中所述苯基經由絲、k 烧氧幾基Hx及”雜賴·鱗如之美4 單取代。 & 5. 如申請專利範圍第4項所述之化合物，其中r2表示Cm烧基-苯基，其中所述苯基經由祕、甲氧幾基、氰基以及胺甲醯基所構成的族群選出之取代基單取代。4. The compound according to claim 3, wherein R2 represents a hydrogen atom, a CM filament, a phenyl group, wherein the phenyl group is exemplified by a wire, a k-oxygen group Hx, and a 5. A compound according to claim 4, wherein r2 represents a Cm alkyl-phenyl group, wherein the phenyl group is formed via a secret group, a methoxy group, a cyano group and an amine formazan group. The substituents selected by the ethnic group are substituted.

6. 如申請專利範圍帛1項至第5項中任-項所述之化合物，其中R3表示視情況經—或兩個選自㈣子、氣原子以及甲基之取代基取代的5至1〇員雜芳基。一 7.如申請專利範圍第6項所述之化合物，其中以表示經兩個氯原子取代之吡啶基。八 8.如申請專利範圍帛！項至第7項中任一項所述之化合物，其中： R1表示窥基； R表不Q_4烷基-苯基，其中所述苯基經由羧基、甲氧羰基、氰基以及胺曱醯基所構成的族群選出之取代基單取 64 201031663 4 λ 代；且 :::經兩個氯原子取代之吼啶基。凊專利範圍第1項所述之化合物，其中 R2表示羥基或胺基； R表示氫原子’甲基、CH2CONH2,吼咬-3-基-甲基， =況經—個由甲氧基、絲、甲氧減、胺甲醯基以及祿所構柄_選*之取代基取代的苯曱基，視情況經個=氰基以及胺甲醯基所構成的族群選出之取代基取代的3_苯丙基，3-(N-嗎啉基)丙基或3_(二曱基胺曱醯基)苯磺醯基； R3表示3,5-二氣吡啶斗基。 10.如申請專利範圍第丨項所述之化合物，其為以下化合物之一： 5-(3,5-二氯吡啶_4_基胺基二甲基-6,7,8,9-四氳 -3Η-σ比口坐並[3,4-c]異嗜琳-1-醇； ρ Ν5-(3,5·二氯吡啶_4_基)_8,8-二甲基-6,7,8,9-四氫·3Η- π比唑並[3,4-c]異喹啉-ο-二胺； 3-(5-(3,5-二氣π比咬_4_基胺基）-1-經基-8,8-二曱基 -6,7,8,9-四氫-3m〇坐並[3,4-c]異唆淋基續醯基)-Ν，Ν-二曱基苯甲醯胺； 5-(3,5-二氯吡啶冰基胺基)-H3-甲氧基苯甲基)_8,8_ 二曱基-6,7,8,9-四氫_311-吼嗤並[3,4-〇]異喹琳-1-醇； 5·(3,5_二氯吡啶_4_基胺基)-3,8，卜三甲基_6,7,8,9-四氫 -3H-吼峻並[3,4-c]異啥琳-1-醇； 65 201031663 3-((5-(3,5-二氣0比唆-4-基胺基)小羥基_8,8_二曱基 -6,7,8,9-四氫-3H-吡唑並P，4-c]異喹琳_3-基）甲基)苯甲酸曱酯； 3-((5-(3,5-二氣0比贫-4-基胺基)小羥基_8,8_二曱基 -6,7,8,9-四氫-3H·吡唑並[3,4-c]異喹琳-3-基）曱基)苯曱酸； 5-(3,5-二氯吡啶-4-基胺基)-8,8-二甲基_3_(吡啶-3-基曱基)-6,7,8,9-四氳^^吼嗤並[3,4-c]異啥琳小醇； 2- (5-(3,5-二氣°比咬-4-基胺基）小經基_8,8_二甲基 -6,7,8,9-四氫-3H-吡唑並[3,4_c]異喹啉-3-基）乙醯胺； 3- ((5-(3,5-二氣〇比唆_4_基胺基)小經基_8,8_二甲基 •6,7,8,9-四氫-3Η·σΛ嗅並[3,4-c]異啥琳_3_基）甲基）苯甲醯胺； 4-((5-(3,5-二氯°比咬-4-基胺基)_ι_經基_8,8_二甲基 -6,7,8,9-四氫-3Η-ΠΛ峻並[3,4_c]異啥琳-3-基）甲基)苯甲酸曱酯； 4-((5-(3,5-二氯吼咬-4-基胺基)_ι_經基_8,8_二甲基 -6,7,8,9-四氫-3H-11比嗤並[3,4，c]異啥琳-3-基）甲基)苯甲酸； 3_((5-(3,5- 一風10比咬-4-基胺基_經基二甲基 -6,7,8,9-四氫-3H-0比唆並[3,4-c]異啥琳-3-基）甲基)苯曱腈； 4-((5-(3,5-二氯吼啶-4-基胺基W _羥基_8,8_二甲基 -6,7,8,9-四氩-3H-吡唑並[3,4-c]異喹啉_3_基）曱基）苯甲醯胺； 5-(3,5-二氣吼啶-4-基胺基)-8,8-二甲基_3-(3-(N-嗎啉基）丙基)-6,7,8,9-四氳-3H-®比嗤並[3,4-c]異啥琳_1_醇； 201031663 - ((5 (3,5 一氣11比咬-4-基胺基)-1-經基_8,8-二甲基 -6,7,8,9-四氫_3H_t坐並[3,4_c]異♦琳_3_基)丙基)苯甲赌了 ((5 (3,5 一風>0比咬-4-基胺基)-1-經基_8,8_二曱基 _6,7,8,9-四氫_3H_吡唑並[3,4_c]異喹啉_3_基）丙基）苯甲^ 胺，或其醫藥學上可接受之鹽或Ν氧化物。 11. 如申請專利範圍第〗項至第1〇項中任一項所述之 © 化合物’其用於治療易藉由抑制鱗酸二醋酶IV來改善之病理學病狀或疾病。 12. 如申請專利範圍第11項所述之化合物，其中所述病理學病狀或疾病是選自哮喘、慢性阻塞性肺病（chr〇nic obstructive pulmonary disease )、過敏性鼻炎（孤物 rhinitis)、類風濕性關節炎（rheumat〇id虹制也）、多發性硬化症（multiple sclerosis )、異位性皮膚炎（at〇pic dermatitis )、牛皮癬或發炎性腸病（inflammat〇w Μ* 泛 disease)。 13. —種醫藥組合物，其包括如申請專利範圍第}項至第10項中任一項所述之化合物以及醫藥學上可接受之稀釋劑或載劑。 14. 一種如申請專利範圍第丨項至第1〇項中任一項所述之化合物的用途’其用於製造供治療如申請專利範圍第 11項或第12項中所定義之病理學病狀或疾病的藥劑。 15. —種治療罹患如申請專利範圍第u項或第^項中所定義之病理學病狀或疾病之個體的方法，其包括向所 67 201031663 項至第1〇項中任述個體投與有效量之如帽糊範圍第1 一項所述之化合物。 16. 種組合產物，其包括同時、分丨$ 、落人辦七叙从胁> ^ 刀別或依序用於治療人體或動物體之⑴如申請專鄕圍g i項至第⑺項中任-項所述之化合物，以及（ii) 一或多種由p2_腎上腺素激導性促效劑（P2-adrenergic ag〇nist )、抗膽鹼劑 (anti-cholinergic)、抗過敏劑（anti_allergic agent)、消炎劑6. The compound of any one of clauses 1 to 5, wherein R3 represents 5 to 1 as the case may be - or two substituents selected from the group consisting of a (tetra), a gas atom and a methyl group. The clerk is heteroaryl. A compound according to claim 6 wherein the pyridyl group substituted with two chlorine atoms is represented. Eight 8. If you apply for a patent scope 帛! The compound of any one of clause 7, wherein: R1 represents a phono group; R represents a Q-4 alkyl-phenyl group, wherein the phenyl group is via a carboxyl group, a methoxycarbonyl group, a cyano group, and an amine sulfhydryl group. The substituents selected by the constituent groups are taken as 64 201031663 4 λ generation; and ::: an acridinyl group substituted by two chlorine atoms. The compound of claim 1, wherein R2 represents a hydroxyl group or an amine group; R represents a hydrogen atom 'methyl, CH2CONH2, 吼-3-yl-methyl, and = methoxy, silk a phenylhydrazine group substituted with a substituent selected from the group consisting of a methoxy group, an amine group, and a substituent selected from the group consisting of a substituent selected from the group consisting of a group consisting of a cyano group and an amine group. Phenylpropyl, 3-(N-morpholinyl)propyl or 3-(didecylaminoindenyl)benzenesulfonyl; R3 represents 3,5-dipyridinyl. 10. The compound of claim 2, which is one of the following compounds: 5-(3,5-dichloropyridine-4-ylaminodimethyl-6,7,8,9-tetra氲-3Η-σ is more than [3,4-c]isoxan-1-ol; ρ Ν5-(3,5·dichloropyridine_4_yl)_8,8-dimethyl-6, 7,8,9-tetrahydro-3Η-π-pyrazolo[3,4-c]isoquinoline-o-diamine; 3-(5-(3,5-two-gas π ratio bite_4_ base Amino)-1-yl-based-8,8-dimercapto-6,7,8,9-tetrahydro-3m oxime[3,4-c]isoindole-based hydrazino)-hydrazine, Ν-dimercaptobenzamide; 5-(3,5-dichloropyridyl amylamino)-H3-methoxybenzyl)_8,8-didecyl-6,7,8,9- Tetrahydro-311-indolo[3,4-indolyl]isoquinolin-1-ol; 5·(3,5-dichloropyridine-4-ylamino)-3,8,ditrimethyl_ 6,7,8,9-tetrahydro-3H-indene[3,4-c]isoindol-1-ol; 65 201031663 3-((5-(3,5-two gas 0 唆- 4-ylamino)small hydroxy-8,8-dimercapto-6,7,8,9-tetrahydro-3H-pyrazolo P,4-c]isoquinoline-3-yl)methyl) Ethyl benzoate; 3-((5-(3,5-diox0-depleted-4-ylamino))-hydroxy-8,8-didecyl-6,7,8,9-tetrahydro- 3H·pyrazolo[3,4-c]isoquinolin-3-yl)indolylbenzoic acid; 5-(3,5-dichloropyridyl Pyridin-4-ylamino)-8,8-dimethyl_3_(pyridin-3-ylindenyl)-6,7,8,9-tetradecyl^^吼嗤[3,4-c] Isoindene small alcohol; 2-(5-(3,5-diox ratio -4-amino-amino) small vial _8,8-dimethyl-6,7,8,9-tetrahydro -3H-pyrazolo[3,4_c]isoquinolin-3-yl)acetamidamine; 3-((5-(3,5-di- gas 〇唆 4 4-amino) yl) 8,8_Dimethyl•6,7,8,9-tetrahydro-3Η·σΛ sniff [3,4-c]isoindolyl_3_yl)methyl)benzamide; 4-( (5-(3,5-Dichloropyran than -4-aminol)_ι_ 经基_8,8-Dimethyl-6,7,8,9-tetrahydro-3Η-ΠΛ峻和[ 3,4_c]isoindol-3-yl)methyl)benzoate oxime; 4-((5-(3,5-dichloropurine-4-ylamino)_ι_经基_8,8 _Dimethyl-6,7,8,9-tetrahydro-3H-11 is more than [3,4,c]isoindol-3-yl)methyl)benzoic acid; 3_((5-(3) , 5-- a wind of 10 to a bit of 4-ylamino-based dimethyl -6,7,8,9-tetrahydro-3H-0 than hydrazine [3,4-c] isoindene-3 -yl)methyl)benzonitrile; 4-((5-(3,5-dichloroacridin-4-ylamino) W_hydroxy_8,8-dimethyl-6,7,8,9 -tetraar-3H-pyrazolo[3,4-c]isoquinoline-3-yl)indenyl)benzamide; 5-(3,5-dioxacridin-4-ylamino) -8,8-Dimethyl_3-(3-(N-? Propyl)-6,7,8,9-tetraindole-3H-® is more than [3,4-c]isoindene-1_ol; 201031663 - ((5 (3,5 one gas 11 ratio)咬-4-ylamino)-1-yl-based -8,8-dimethyl-6,7,8,9-tetrahydro-3H_t sits and [3,4_c]iso ♦lin_3_yl) Benzo) bet gambling ((5 (3,5 a wind > 0 to bite-4-ylamino)-1-yl group _8,8_didecyl _6,7,8,9-four Hydrogen_3H-pyrazolo[3,4_c]isoquinolin-3-yl)propyl)benzamide, or a pharmaceutically acceptable salt or cerium oxide thereof. 11. The compound according to any one of the preceding claims, wherein the compound is used for the treatment of a pathological condition or disease which is easily ameliorated by inhibition of bisphosphonate IV. 12. The compound of claim 11, wherein the pathological condition or disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (chr〇nic obstructive pulmonary disease), allergic rhinitis (orphan rhinitis), Rheumatoid arthritis (rheumat〇id rainbow system), multiple sclerosis, at〇pic dermatitis, psoriasis or inflammatory bowel disease (inflammat〇w Μ* pan-disease) . A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, and a pharmaceutically acceptable diluent or carrier. 14. Use of a compound according to any one of claims 1 to 1 which is used for the manufacture of a pathological disease as defined in claim 11 or 12 of the patent application. An agent for a disease or disease. 15. A method of treating an individual suffering from a pathological condition or disease as defined in the scope of claim 5 or claim 2, comprising administering to any of the individuals in the group of 2010, 2010, 663, 663 An effective amount of a compound as described in the first item of the cap paste range. 16. A combination product, which includes simultaneous, splitting, and falling, and arranging for the treatment of the human or animal body (1) if applying for a special gi item to item (7) a compound according to any one of the items, and (ii) one or more of a p2-adrenergic ag〇nist, an anti-cholinergic, an anti-allergic agent (anti_allergic) Agent)

(anti-inflammatory agent )、免疫抑制劑以及抗感染劑 (anti-infective agent)所構成的族群選出之活性成份。〇 68 201031663 f 四、指定代表圖： (一）本案之指定代表圖：無 (二）本代表圖之元件符號簡單說明：五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：An active ingredient selected from the group consisting of an anti-inflammatory agent, an immunosuppressive agent, and an anti-infective agent. 〇 68 201031663 f IV. Designated representative map: (1) The designated representative figure of the case: None (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention:

式⑴Formula (1)

33